JP2003534230A - 1,3-benzodiazepin-2-one and 1,3-benzoxazepin-2-one useful as HIV reverse transcriptase inhibitors - Google Patents

Abstract

(57) Abstract: The present invention relates to 1,3-benzodiazepin-2-ones and 1,3-benzoxazepin-2-ones of the formula (I) useful as inhibitors of HIV reverse transcriptase or Stereoisomers, stereoisomeric mixtures, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions and diagnostic kits containing them, and methods of using them for the treatment of viral infections or as assay standards or reagents About. Embedded image

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention generally relates to 1,3-benzodiazepin-2-ones and 1,3-benzoxazepin-2-ones, useful as inhibitors of HIV reverse transcriptase, and pharmaceuticals containing them. It relates to compositions and diagnostic kits, methods of using it for the treatment of viral infections or as assay standards or reagents, as well as intermediates and processes for their preparation.

BACKGROUND OF THE INVENTION Two different retroviruses, the human immunodeficiency virus (HIV) type 1 (HIV).
-1) or type 2 (HIV-2) is etiologically associated with an immunosuppressive disease, acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic, but generally develop AIDS-related syndrome (ARC), followed by AIDS.
Affected individuals exhibit a severe immunosuppressive state that is debilitating and ultimately susceptible to deadly opportunistic infections.

The disease AIDS is a unique and complex life cycle of HIV-1 or HIV.
-2 is the final result of the virus. The life cycle of this virion is that the glycoprotein on the surface of the virion protective membrane binds to the CD4 glycoprotein on lymphocyte cells,
It begins with the attachment of the virion itself to host human T-4 lymphocyte immune cells. Once attached, the virion breaks off its glycoprotein membrane and penetrates into the host cell membrane, exposing its RNA. The virion enzyme, reverse transcriptase, directs the transcription of RNA into single-stranded DNA. This viral RNA is degraded and the second DNA
A chain is created. This double-stranded DNA is then integrated into human cell genes and these genes are used for viral replication.

At this point, RNA polymerase transcribes the incorporated DNA into viral RNA. This viral RNA is translated into the precursor gag-pol fusion polyprotein. This polyprotein is then cleaved by the HIV protease enzyme to give the mature viral protein. Therefore, HIV protease is responsible for controlling the cascade of cleavage events that matures the viral particle into a fully infectious virus.

This virus infects and kills T cells of the immune system, thus placing a heavy load on the general human immune system response that kills invading virions. Furthermore, the viral reverse transcriptase, the enzyme used to form new virion particles, is not very specific and causes transcriptional errors that frequently alter glycoproteins on the viral protective membrane surface. Let Due to this lack of specificity, antibodies specifically produced against one glycoprotein may not be useful for others, thus reducing the number of antibodies available to fight the virus. Therefore, the effectiveness of the immune system is reduced. While the immune response system continues to weaken, viral replication continues. Finally, HIV controls the body's immune system almost freely, causing opportunistic infections and can be fatal without the administration of antiviral agents, immunomodulators, or both.

At least three important points that can be recognized as targets of antiviral agents in the viral life cycle: (1) initial attachment of virions to T-4 lymphocyte or macrophage sites; (2) from viral RNA Transcription into viral DNA (reverse transcriptase, R
T), and (3) there is processing of the gag-pol protein by HIV protease.

[0007] A second important point, inhibition of the virus in the process of transcription of viral RNA into viral DNA, provides some of the current therapies used in the eradication of AIDS. Since the virion gene is encoded by RNA and the host cell reads only DNA, this transcription must be done for the virion to replicate. HIV-1 replication can be stopped by introducing an agent that blocks this reverse transcriptase from completing the formation of viral DNA.

Several compounds that interfere with viral replication have been developed for the treatment of AIDS. For example, 3'-azido-3'-deoxythymidine (AZT), 2 ',
3'-dideoxycytidine (ddC), 2 ', 3'-dideoxythymidine (d4
T), nucleotide analogs such as 2 ', 3'-dideoxyinosine (ddI), and 2', 3'-dideoxy-3'-thia-cytidine (3TC), are HIV-reversed at the reverse transcriptase (RT) step. It has been shown to be relatively effective in stopping replication.

An active area of research is the discovery of non-nucleoside HIV reverse transcriptase inhibitors.
By way of example, certain benzoxazinones and quinazolinones have been found to be active in inhibiting HIV reverse transcriptase, preventing or treating infection by HIV and treating AIDS.

US Pat. No. 5,915,021 describes reverse transcriptase inhibitors which are benzoxazinones of the formula:

[0011]

[Chemical 4]

[0012]     In the formula, X may be halogen and Z may be O.

EP 0530994 and WO 93/04047 describe HIV reverse transcriptase inhibitors which are quinazolinones of formula A.

[0014]

[Chemical 5]

Wherein G is various groups, R ₃ and R ₄ can be H, Z can be O, and R ²
Is unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycle, and optionally substituted aryl, and R ¹ can be various groups including substituted alkyl.

WO95 / 12583 also describes HIV reverse transcriptase inhibitors of formula A. In this publication, G is various groups, R ³ and R ⁴ can be H, Z
Can be O, R ² is substituted alkenyl or substituted alkynyl, and R ¹ is cycloalkyl, alkynyl, alkenyl, or cyano. WO95 / 1327
3 is one of the compounds of WO95 / 12583, (S)-(-)-6-chloro-4.
-Cyclopropyl-3,4-dihydro-4 ((2-pyridyl) ethynyl) -2 (
Illustrates the asymmetric synthesis of 1H) -quinazolinones.

Synthetic procedures for making such quinazolinones are detailed in the following references: "Houpis et al, Tetr. Lett. 1994, 35 (37.
), 6811-6814 "," Tucker et al, J. Med. Che.
m. 1994, 37, 2437-2444 ", and" Huffman et.
al, J. Org. Chem. 1995, 60, 1590-1594 ".

[0018]   DE 4320347 exemplifies quinazolinones of the formula:

[0019]

[Chemical 6]

In the formula, R is phenyl, carbocycle, or heterocycle. This class of compounds is not considered part of this invention.

It has been found that HIV patients can be resistant to a single inhibitor even with the currently successful and successful reverse transcriptase inhibitors. Therefore, the development of additional inhibitors is desired to further combat HIV infection.

SUMMARY OF THE INVENTION Accordingly, one object of the present invention is to provide novel reverse transcriptase inhibitors.

Another object of the invention is a novel method of treating HIV infection, wherein a therapeutically effective amount of at least one compound of the invention, or a pharmaceutically acceptable salt thereof, is administered to such treatment. It is to provide a method comprising administering to a host in need thereof.

Another object of the invention is a novel method of treating HIV infection, which comprises (a) one of the compounds of the invention and (b) an HIV reverse transcriptase inhibitor and an HIV protease inhibitor. It is to provide a method comprising administering a pharmaceutically effective combination of one or more compounds selected from the group to a host in need of such treatment.

Another object of the invention is a pharmaceutical composition having reverse transcriptase inhibitory activity, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of the invention or a pharmaceutically acceptable salt thereof. It is to provide things.

Another object of the invention is to provide a method of inhibiting HIV present in body fluids, which method comprises treating a body fluid sample with an effective amount of a compound of the invention.

Another object of the present invention is that it is useful for use as a standard or reagent in a test or assay that measures the ability of an agent to inhibit HIV reverse transcriptase, HIV proliferation or both. To provide a kit or container containing an amount of at least one compound of the invention.

Another object of the invention is to provide novel compounds for use in therapy.

Another object of the invention is to provide the use of the novel compounds for the manufacture of a medicament for the treatment of HIV.

These and other objects that will become apparent in the detailed description below are of formula (I)
This is achieved by the present inventors' discovery that the compounds of the present invention, their stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof are effective reverse transcriptase inhibitors.

[0031]

[Chemical 7]

However, R ¹ , R ² , R ³ , X, and Y are as defined below.

[0033]     (Details of preferred embodiment) [1] Accordingly, in one embodiment, the present invention provides a novel compound of formula I:

[0034]

[Chemical 8]

Alternatively, it provides a stereoisomer thereof or a pharmaceutically acceptable salt form thereof.
Wherein A is O or S, B is selected from O, S, and NR ⁸ , W is N or CR ³ , X is N or CR ^3a , Y is N or CR ^3b , Z is N or CR ^3c , provided that when two of W, X, Y, and Z are N, the rest are other than N, and R ¹ is substituted with 0 to 7 halogens. is selected from C _{1 ~ 3} alkyl group and cyclopropyl, R ^{2 is, -R 2c, -OR 2c, -OCHR} 2a R 2b, -OCH 2 CHR 2a R 2b, -O (
CH ₂ ) ₂ CHR ^2a R ^2b , -OCHR ^2a C = C-R ^2b , -OCHR ^2a C = R ^2c ,-
^{OCHR 2a C≡C-R 2b, -SR} 2c, -SCHR 2a R 2b, -SCH 2 CHR 2a R 2 b, -S (CH 2) 2 CHR 2a R 2b, -SCHR 2a C = C-R 2b, -SCHR2 ^a C
^{= R 2c, -SCHR 2a C≡C-} R 2b, -NR 2a R 2c, -NHCHR 2a R 2b, -N
_{^{HCH 2 CHR 2a R 2b, -NH}} (CH 2) 2 CHR 2a R 2b, -NHCHR 2a C = C
—R ^2b , —NHCHR ^2a C═R ^2c , and —NHCHR ^2a C≡C—R ^2b , wherein R ^2a is H, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , and CH. is selected from the group of ₂ CH ₂ CH _3, R ^2b is H or R ^2C, R ^2c is 0-2 C _{1 ~ 6} alkyl substituted with R ^4, substituted with 0-2 R ⁴ has been C _{2 - 5} alkenyl, 0-1 R ⁴ C _{2 - 5} alkynyl substituted with, 0-2 C ₃ substituted with R ^3d of _1-6 cycloalkyl, 0-2 R ^3d A phenyl substituted with
And 1 to 3 heteroatoms selected from the group of O, N, and S,
Selected from the group of 3 to 6 membered heterocyclic groups substituted with 2 R ^3d , or, alternatively, the —NR ^2a R ^2c group has 0 to 1 carbon atom substituted with O or NR ⁵ . represents a 4-7 membered cyclic amine, R ³ is H, C _{1 ~ 4} alkyl, -OH, C _{1 ~ 4 alkoxy, OCF 3, F, Cl,} B
^{r, I, -NR 5 R 5a} , -NO 2, -CN, -C (O) R 6, -NHC (O) R 7,
^{-NHC (O) NR 5 R 5a} , -NHSO 2 R 10, -SO 2 NR 5 R 5a, and O, N
, And is selected from the group of 5- to 6-membered heteroaromatic ring containing 1-4 heteroatoms selected from the group of S, R ^3a is H, C _{1 ~ 4} alkyl, -OH, C _{1 ~ 4} alkoxy, OCF ₃ , F, Cl,
^{Br, I, -NR 5 R 5a} , -NO 2, -CN, -C (O) R 6, -NHC (O) R 7, -NHC (O) NR 5 R 5a, -NHSO 2 R 10, - SO ₂ NR ⁵ R ^5a , and O,
Selected from the group of 5 to 6 membered heteroaromatic rings containing 1 to 4 heteroatoms selected from the group of N, and S, or alternatively, R ³ and R ^3a together represent —OCH ₂ O— formed, R ^3b is H, C _{1 ~ 4} alkyl, -OH, C _{1 ~ 4} alkoxy, OCF _3, F, Cl,
^{Br, I, -NR 5 R 5a} , -NO 2, -CN, -C (O) R 6, -NHC (O) R 7, -NHC (O) NR 5 R 5a, -NHSO 2 R 10 and, It is selected from the group of -SO ₂ NR ⁵ R ^5a, or, R ^3a and R ^3b are formed a -OCH ₂ O-together, R ^3c is, H, C _{1 ~ 4} alkyl, -OH, C _{1 ~ 4} Alkoxy, OCF ₃ , F, Cl
^{, Br, I, -NR 5 R} 5a, -NO 2, -CN, -C (O) R 6, -NHC (O)
R ⁷ , —NHC (O) NR ⁵ R ^5a , —NHSO ₂ R ¹⁰ , and —SO ₂ NR ⁵ R ^5a , or R ^3b and R ^3c together form —OCH ₂ O—. and, for each R ^3d is appearing, C _{1 ~ 4} alkyl, -OH, C _{1 ~ 4} alkoxy, OCF _3,
F, Cl, Br, I, -NR 5 R 5a, -NO 2, -CN, -C (O) R 6, -NH
^{C (O) R 7, -NHC} (O) NR 5 R 5a, -NHSO 2 R 10, and -SO ₂ NR ⁵ independently from the group consisting of R ^5a is selected, each R ^3e is appearing, C _{1 1-4} alkyl, -OH, C _{1 - 4} alkoxy, OCF _3,
F, Cl, Br, I, -NR 5 R 5a, -NO 2, -CN, -C (O) R 6, -NH
^{C (O) R 7, -NHC} (O) NR 5 R 5a, -NHSO 2 R 10, and -SO ₂ NR ⁵ independently from the group consisting of R ^5a is selected, each R ^3f is appearing, C _{1 1-4} alkyl, -OH, C _{1 - 4} alkoxy, OCF _3,
F, Cl, Br, I, -NR 5 R 5a, -NO 2, -CN, -C (O) R 6, -NH
^{C (O) R 7, -NHC} (O) NR 5 R 5a, -NHSO 2 R 10, and -SO ₂ NR ⁵ independently from the group consisting of R ^5a is selected for each the R ^3g appearing, C _{1 1-4} alkyl, -OH, C _{1 - 4} alkoxy, OCF _3,
F, Cl, Br, I, -NR 5 R 5a, -NO 2, -CN, -C (O) R 6, -NH
^{C (O) R 7, -NHC} (O) NR 5 R 5a, -NHSO 2 R 10, -SO 2 NR 5 R 5a
Comprises 0-3 C _{3 ~ 10} carbocyclic and O substituted with R ^3f, N, and 1-3 heteroatoms selected from the group of S, substituted with 0-3 R ^3f 5-10 done
Are independently selected from the group of membered heterocyclic group, R ⁴ is, F, Cl, Br, I , 0~2 amino C _{1 ~ 6} alkyl substituted with R ^3e, 0
To 2 pieces of C _{3 ~ 10} carbocyclic ring substituted with R ^3e, comprises 0-5 phenyl substituted with R ^3e, and O, and 1-3 heteroatoms selected from N and S, 0-2
Is selected from the group of heterocyclic groups substituted 5-10 membered by number of R ^3e, R ⁵ and R ^5a are independently selected from the group of H and C _{1 ~ 4} alkyl, or, R ⁵ and R ^5a together with the nitrogen attached to them are 0
To form a 5- or 6-membered ring containing ~ 1 one O or N atom, R ⁶ is, H, OH, is selected from the group of C _{1 ~ 4} alkyl, C _{1 ~ 4} alkoxy, and NR ⁵ R ^5a, R ⁷ is selected from the group of C _{1 ~ 3} alkyl and C _{1 ~ 3} alkoxy, R ^{8 is, H, oR 9, SR 9} , NR 5 R 9, substituted with 0-3 R ^{3 g} C _1-6 alkyl, 0-3 C _{2 ~ 6} alkenyl substituted with R ^{3 g,} 0-3 C _{2 ~ 6} alkynyl substituted with R ^{3 g,} substituted with 0-2 R ^3f C _{3 ~ 5} cycloalkyl, 0
Phenyl substituted with ~ 5 R ^3f , and 5-6 members substituted with 0-2 R ^3f containing 1-3 heteroatoms selected from the group O, N, and S. is selected from the group of the heterocyclic group, R ⁹ is 1-3 heteroatoms selected from the group of 0-5 C _{3 ~ 10} carbocyclic and O substituted with R ^3f, N, and S 5 containing an atom and substituted with 0-2 R ^3f
Is selected from the group of 10-membered heterocyclic group, R ¹⁰ is selected from C _{1 ~ 4} alkyl and phenyl.

[0036] In [2] a preferred embodiment, the present invention is a novel compound of Formula I, B is NR ^8, R ¹ is a C _{1 ~ 3} alkyl and was substituted with 1-7 halogens Selected from the group of cyclopropyl, R ² is —R ^2c , —OR ^2c , —OCHR ^2a R ^2b , —OCH ₂ CHR ^2a R ^2b , —O (
CH ₂ ) ₂ CHR ^2a R ^2b , -OCHR ^2a C = C-R ^2b , -OCHR ^2a C = R ^2c ,-
^{OCHR 2a C≡C-R 2b, -SR} 2c, -SCHR 2a R 2b, -SCH 2 CHR 2a R 2 b, -S (CH 2) 2 CHR 2a R 2b, -SCHR 2a C = C-R 2b, -SCHR ^2a C
═R ^2c , and —SCHR ^2a C≡C—R ^2b , wherein R ^2a is H, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , and CH ₂ CH ₂ CH ₃ is selected, R ^2b is H or R ^2c, R ^2c is 0-2 C _{1 ~ 5} alkyl substituted with R ^4, C _{2 ~ 5} substituted with 0-2 R ⁴ alkenyl, 0-1 C _{2 ~ 5} alkynyl substituted with R ^4, 0-2 C substituted with R ^3d _{3 ~ 6} cycloalkyl, and substituted with 0-2 R ^3d phenyl is selected from the group of, for each R ³ is appearing, H, C _{1 ~ 4} alkyl, OH, C _{1 ~ 4} alkoxy, F, Cl
^{, Br, I, NR 5 R} 5a, NO 2, -CN, C (O) R 6, NHC (O) R 7, NH
C (O) NR ⁵ R ^5a and independently selected from the group of 5 to 6 membered heteroaromatic rings containing 1 to 4 heteroatoms selected from the group of O, N and S, R ^3a in each occurrence, H, C _{1 ~ 4} alkyl, -OH, C _{1 ~ 4} alkoxy, F, C
1, Br, I, NR ⁵ R ^5a , NO ₂ , —CN, C (O) R ⁶ , NHC (O) R ⁷ , N
HC (O) NR ⁵ R ^5a and independently selected from the group of 5 to 6 membered heteroaromatic rings containing 1 to 4 heteroatoms selected from the group of O, N and S, or , R ³ and R ^3a form a -OCH ₂ O-together, each is R ^3b appearing, H, C _{1 ~ 4} alkyl, OH, C _{1 ~ 4} alkoxy, F, Cl
, Br, I, NR ⁵ R ^5a , NO ₂ , —CN, C (O) R ⁶ , NHC (O) R ⁷ , and NHC (O) NR ⁵ R ^5a independently selected, or, R ^3a and R ^3b form a -OCH ₂ O-together, R ⁴ is, Cl, F, 0~2 amino C _{1 ~ 4} alkyl substituted with R ^3e, 0 to 2 amino R ^{3 e} in substituted C _{3 ~ 5} carbon ring, phenyl substituted with 0-5 R ^3e, and O
, N, and S selected from the group of 5 to 6 membered heterocyclic groups containing 1 to 3 heteroatoms selected from the group substituted with 0 to 2 R ^3e , R ⁵ and R ^5a is independently selected from the group of H, CH ₃ and C ₂ H ₅ , R ⁶ is of H, OH, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ , and NR ⁵ R ^5a . Selected from the group, R ⁷ is CH ₃ , C ₂ H ₅ , CH (CH ₃ ) ₂ , OCH ₃ , OC ₂ H ₅ , and OCH (C
H ₃ ) ₂ and R ⁸ provides a compound selected from the group of H, cyclopropyl, CH ₃ , C ₂ H ₅ , and CH (CH ₃ ) ₂ .

[3] In a further preferred embodiment, the invention is a novel compound of formula I, wherein R ¹ is selected from the group CF ₃ , C ₂ F ₅ and cyclopropyl, and R ² is R ^2c , -OR ^2c , -OCHR ^2a R ^2b , -OCH ₂ CHR ^2a R ^2b , -OC
HR ^2a C = C-R ^2b , -OCHR ^2a C = R ^2c , -OCHR ^2a C≡C-R ^2b , -S
^{R 2c, -SCHR 2a R 2b,} -SCH 2 CHR 2a R 2b, -SCHR 2a C = C-R 2b
, -SCHR ^2a C = R ^2c , and -SCHR ^2a C≡C-R ^2b ,
R ^2a is selected from H, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , and CH ₂ CH ₂ CH ₃ , R ^2b is H or R ^2c , and R ^2c is 0 to 2 R C _{1 ~ 3} alkyl substituted with ^4, 0-2 C _{2 ~ 3} alkenyl substituted with R ^4, 0 to 1 amino C _{2 ~ 3} alkynyl substituted with R ^4, and 0
A two C _{3 ~ 6} cycloalkyl substituted with R ^3d, each R ³ is Degen, H, C _{1 ~ 3} alkyl, OH, C _{1 ~ 3} alkoxy, F, Cl
^{, Br, I, NR 5 R} 5a, NO 2, -CN, C (O) R 6, NHC (O) R 7, NH
Independently selected from the group of C (O) NR ⁵ R ^5a , or R ³ and R ^3a together form —OCH ₂ O—, R ^3b is H, R ^3c is H, each R ^3e is appearing, H, C _{1 ~ 4} alkyl, -OH, C _{1 ~ 4 alkoxy, OCF 3, F, Cl,} -NR 5 R 5a, -C (O) R 6, -SO 2 NR ⁵ is independently selected from the group of R ^5a, R ⁴ is, Cl, F, 0~1 amino C _{1 ~ 4} alkyl substituted with R ^3e, C substituted with 0-2 R ^{3 e} _3-5 carbocycle and 0-2 phenyl substituted with R ^3e, O
, N, and S selected from the group of 5 to 6 membered heterocyclic groups containing 1 to 3 heteroatoms selected from the group substituted with 0 to 1 R ^3e , R ⁵ and R ^5a is independently selected from the group of H, CH ₃ and C ₂ H ₅ , and R ⁶ is a group of H, OH, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ , and NR ⁵ R ^5a . R ⁷ is selected from the group of CH ₃ , C ₂ H ₅ , OCH ₃ and OC ₂ H ₅ , and R ⁸ is selected from the group of H, cyclopropyl, CH ₃ and C ₂ H ₅ . Provide compounds of choice.

[4] In a further preferred embodiment, the invention is a novel compound of formula I, wherein R ¹ is CF ₃ , R ² is —R ^2c , —OR ^2c , —OCH _{2 ^{R 2b, -OCH 2 CH 2 R}} 2b, -OCH 2 C =
_{^{C-R 2b, -OCH 2 C≡C}} -R 2b, -SR 2c, -SCH 2 R 2b, -SCH 2 CH 2 R 2b, -SCH 2 C = C-R 2b, and -SCH ₂ C [identical to] C is selected from the group of -R ^2b, ethyl R ^2b is H or R ^2c, R ^2c is substituted methyl substituted with 0-2 R ^4, with 0-2 R ^4,
0-2 propyl substituted with R ^4, ethenyl substituted with 0-2 R ^4, 0
To 2 amino been 1-propenyl substituted with R ^4, 0-2 is 2-propenyl substituted with R ^4, ethynyl substituted with 0-2 R ^4, with 0-2 R ⁴ 1-replaced
Propynyl, selected from the group of 0-2 R ⁴ in substituted 2-propynyl, and 0-1 R ^{3 d} in substituted cyclopropyl, each R ³ is appearing, C _{1 ~ 3} alkyl, OH, C _{1 ~ 3} alkoxy, F, Cl, N
R ⁵ R ^5a, NO _2, are independently selected -CN, and from the group of C (O) R ^6, or, R ³ and R ^3a form a -OCH ₂ O-together, R ^3d emergence CH ₃ , —OH, OCH ₃ , OCF ₃ , F, Cl, and −
Independently selected from the group of NR ⁵ R ^5a , each occurrence of R ^3e is CH ₃ , —OH, OCH ₃ , OCF ₃ , F, Cl, and —
NR ⁵ are independently selected from the group of R ^5a, R ⁴ _{is, Cl, F, CH 3,} CH 2 CH 3, 0~1 amino cyclopropyl substituted with R ^3e, 0 to 1 amino R ^3e in substituted 1-methyl - cyclopropyl, cyclobutyl substituted with 0-1 R ^3e, phenyl substituted with 0-2 R ^3e, and O
, N, and S containing 1 to 3 heteroatoms selected from the group selected from the group of 5 to 6 membered heterocyclic groups substituted with 0 to 1 R ^3e Is selected from the group of 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, and 2-imidazolyl. , R ⁵ and R ^5a are independently selected from the group of H, CH ₃ and C ₂ H ₅ , R ⁶ is H, OH, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ , And NR ⁵ R ^5a , R ⁷ is selected from the group of CH ₃ , C ₂ H ₅ , OCH ₃ , and OC ₂ H ₅ , and
R ⁸ is selected from the group of H, cyclopropyl, and C ₂ H ₅ .

[0039] [5] In a further preferred embodiment, the compound is of formula Ia.

[0040]

[Chemical 9]

[0041] [6] In a further preferred embodiment, the compound is of formula Ib.

[0042]

[Chemical 10]

[7] In a further preferred embodiment, the compound of formula I is 7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-5-
(Trifluoromethyl) -1,3-benzodiazepin-2-one, 6,7-difluoro-5- (2-cyclopropylethynyl) -1,5-dihydro-5- (trifluoromethyl) -1,3- Benzodiazepin-2-one, 7-chloro-5- (2-cyclopropylethenyl) -1,5-dihydro-5-
(Trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-5-
(Trifluoromethyl) -1,3-benzodiazepine-2-thione, 7-chloro-5- (2-n-butyl) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine- 2-one, 7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-3-
Methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-3-
Ethyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-3-
Cyclopropyl-5- (trifluoromethyl) -1,3-benzodiazepine-2
-One, 7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (3 -Methyl-2-butenyloxy) -1,5-dihydro-
3-Methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (3-allyloxy) -1,5-dihydro-3-methyl-5
-(Trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (3,3-dichloro-2-propenyloxy) -1,5-dihydro-3-methyl-5- (tri Fluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (2-propynyloxy) -1,5-dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepine -2-one, 7-chloro-5- (2-fluoro-6-methoxybenzyloxy) -1,5-
Dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (cyclopropylmethyloxy) -1,5-dihydro-5-
(Trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (cyclopropylmethyloxy) -1,5-dihydro-5- (trifluoromethyl) -1,3 -Benzodiazepin-2-one, 7-chloro-3-cyclopropyl-5- (cyclopropylmethoxy) -1,5
-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-3-cyclopropyl-5- (cyclopropylmethoxy)
-1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-cyclopropyl-5-propyloxy-1,5-dihydro-
5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-cyclopropyl-5-propylthio-1,5-dihydro-5
-(Trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-cyclopropyl-5-allylthio-1,5-dihydro-5-
(Trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-cyclopropyl-5-allyloxy-1,5-dihydro-5
-(Trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-cyclopropyl-5- (3-methyl-2-butenyloxy)
-1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-cyclopropyl-5-cyclobutylmethyloxy-1,5-
Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-cyclopropyl-5- (1-methylcyclopropyl) methyloxy-1,5-dihydro-5- ( Trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-cyclopropyl-5- (2-pyridyl) methyloxy-1,
5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-2-
ON, 7-chloro-3-isopropyl-5-cyclopropylmethyloxy-1,5-
Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-cyclobutyl-5-cyclopropylmethyloxy-1,5-
Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (cyclopropylmethoxy) -1,5-dihydro-3-ethyl-5- (trifluoromethyl)- 1,3-benzodiazepin-2-one, (S) -7-chloro-5- (cyclopropylmethyloxy) -1,5-dihydro-3-ethyl-5- (trifluoromethyl) -1,3-benzodiazepine -2
-One, 7-chloro-3-ethyl-5- (3-methyl-2-butenyloxy) -1,5
-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-ethyl-5-allylthio-1,5-dihydro-5- (trifluoromethyl) -1,3 -Benzodiazepin-2-one, 7-chloro-3-ethyl-5-cyclobutylmethyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro- 3-Ethyl-5-cyclopropylmethylthio-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-ethyl-5- (1-methylcyclopropyl ) Methyloxy-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, 7-chloro-3-propyl-5-cyclopropylmethyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-fluoro-5- ( Cyclopropylmethoxy) -1,5-dihydro-5- (
Trifluoromethyl) -1,3-benzodiazepin-2-one, 7-fluoro-3-ethyl-5-cyclopropylmethyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine- 2-one, 7-fluoro-5- (cyclobutylmethoxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-fluoro-3-ethyl-5- Cyclobutylmethyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- [2- (1-methylcyclopropyl) ethynyl] -1, 5-
Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5-cyclobutylmethyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine -2-one, 7-chloro-5- (3-methyl-2-butenyloxy) -1,5-dihydro-
5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (phenylmethyloxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine- 2-one, 7-chloro-5-[(2-pyridyl) methyloxy] -1,5-dihydro-5
-(Trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5-[(1-methylcyclopropyl) methyloxy] -1,5-
Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (3-methylphenyloxy) -1,5-dihydro-5- (
Trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (cyclopropylmethylthio) -1,5-dihydro-5- (
Trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (propylthio) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, and From the group of 7-chloro-5- (2-propenylthio) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one or their pharmaceutically acceptable salt forms To be selected.

[8] In yet another preferred embodiment, the compound of formula I is (S) -7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-5- (trifluoromethyl ) -1,3-Benzodiazepin-2-one, (S) -6,7-difluoro-5- (2-cyclopropylethynyl) -1,5
-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (2-cyclopropylethenyl) -1,5-dihydro-5- (tri Fluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-5- (trifluoromethyl) -1,3- Benzodiazepine-2-thione, (S) -7-chloro-5- (2-n-butyl) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S ) -7-Chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepine-2
-One, (S) -7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-3-ethyl-5- (trifluoromethyl) -1,3-benzodiazepine-2
-One, (S) -7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-3-cyclopropyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-Chloro-5-cyclopropylmethyloxy-1,5-dihydro-
3-Methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (3-methyl-2-butenyloxy) -1,5-dihydro-3- Methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (3-allyloxy) -1,5-dihydro-3-methyl-5- (tri Fluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (3,3-dichloro-2-propenyloxy) -1
, 5-Dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (2-propynyloxy) -1,5-dihydro- Three
-Methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (2-fluoro-6-methoxybenzyloxy)-
1,5-dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (cyclopropylmethyloxy) -1,5-dihydro -5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (cyclopropylmethyloxy) -1,5-dihydro-5- (trifluoromethyl)- 1,3-benzodiazepin-2-one, (S) -7-chloro-3-cyclopropyl-5- (cyclopropylmethoxy)
-1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-3-cyclopropyl-5- (cyclopropylmethoxy)
-1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-3-cyclopropyl-5-propyloxy-1,5-dihydro-5 -(Trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-3-cyclopropyl-5-propylthio-1,5-dihydro-5- (trifluoromethyl) -1, 3-benzodiazepin-2-one, (S) -7-chloro-3-cyclopropyl-5-allylthio-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, ( S) -7-chloro-3-cyclopropyl-5-allyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro 3-Cyclopropyl-5- (3-methyl-2-butenyloxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-3 -Cyclopropyl-5-cyclobutylmethyloxy-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, (S) -7-chloro-3-cyclopropyl-5- (1-methylcyclopropyl) methyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-2 -One, (S) -7-chloro-3-cyclopropyl-5- (2-pyridyl) methyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-Chloro-3-isopropyl-5-cyclopropylmethyloxy-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, (S) -7-chloro-3-cyclobutyl-5-cyclopropylmethyloxy-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, (S) -7-chloro-5- (cyclopropylmethoxy) -1,5-dihydro-
3-Ethyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (cyclopropylmethyloxy) -1,5-dihydro-3-ethyl-5 -(Trifluoromethyl) -1,3-benzodiazepine-2
-One, (S) -7-chloro-3-ethyl-5- (3-methyl-2-butenyloxy)
-1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-3-ethyl-5-allylthio-1,5-dihydro-5-
(Trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-3-ethyl-5-cyclobutylmethyloxy-1,5-
Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-3-ethyl-5-cyclopropylmethylthio-1,5-
Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-3-ethyl-5- (1-methylcyclopropyl) methyloxy-1,5-dihydro- 5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-3-propyl-5-cyclopropylmethyloxy-1,
5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-2-
On, (S) -7-fluoro-5- (cyclopropylmethoxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-fluoro- 3-ethyl-5-cyclopropylmethyloxy-1,
5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-2-
ON, (S) -7-fluoro-5- (cyclobutylmethoxy) -1,5-dihydro-
5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-fluoro-3-ethyl-5-cyclobutylmethyloxy-1,5
-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- [2- (1-methylcyclopropyl) ethynyl]-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, (S) -7-chloro-5-cyclobutylmethyloxy-1,5-dihydro-5
-(Trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (3-methyl-2-butenyloxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (phenylmethyloxy) -1,5-dihydro-5
-(Trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5-[(2-pyridyl) methyloxy] -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5-[(1-methylcyclopropyl) methyloxy]-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, (S) -7-chloro-5- (3-methylphenyloxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S)- 7-chloro-5- (cyclopropylmethylthio) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (propylthio)- 1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, and (S) -7-chloro-5- (2-propenylthio) -1,5-dihydro-5-
It is selected from the group of (trifluoromethyl) -1,3-benzodiazepin-2-ones or their pharmaceutically acceptable salt forms.

[9] In yet another preferred embodiment, the compound of formula I is (R) -7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-5- (trifluoromethyl ) -1,3-Benzodiazepin-2-one, (R) -6,7-difluoro-5- (2-cyclopropylethynyl) -1,5
-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (2-cyclopropylethenyl) -1,5-dihydro-5- (tri Fluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-5- (trifluoromethyl) -1,3- Benzodiazepine-2-thione, (R) -7-chloro-5- (2-n-butyl) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R ) -7-Chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepine-2
-One, (R) -7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-3-ethyl-5- (trifluoromethyl) -1,3-benzodiazepine-2
-One, (R) -7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-3-cyclopropyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-
3-Methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (3-methyl-2-butenyloxy) -1,5-dihydro-3- Methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (3-allyloxy) -1,5-dihydro-3-methyl-5- (tri Fluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (3,3-dichloro-2-propenyloxy) -1
, 5-Dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (2-propynyloxy) -1,5-dihydro- Three
-Methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (2-fluoro-6-methoxybenzyloxy)-
1,5-dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (cyclopropylmethyloxy) -1,5-dihydro -5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (cyclopropylmethyloxy) -1,5-dihydro-5- (trifluoromethyl)- 1,3-benzodiazepin-2-one, (R) -7-chloro-3-cyclopropyl-5- (cyclopropylmethoxy)
-1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-3-cyclopropyl-5- (cyclopropylmethoxy)
-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-3-cyclopropyl-5-propyloxy-1,5-dihydro-5 -(Trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-3-cyclopropyl-5-propylthio-1,5-dihydro-5- (trifluoromethyl) -1, 3-benzodiazepin-2-one, (R) -7-chloro-3-cyclopropyl-5-allylthio-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, ( R) -7-Chloro-3-cyclopropyl-5-allyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro 3-Cyclopropyl-5- (3-methyl-2-butenyloxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-3 -Cyclopropyl-5-cyclobutylmethyloxy-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, (R) -7-chloro-3-cyclopropyl-5- (1-methylcyclopropyl) methyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-2 -One, (R) -7-chloro-3-cyclopropyl-5- (2-pyridyl) methyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-3-isopropyl-5-cyclopropylmethyloxy-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, (R) -7-chloro-3-cyclobutyl-5-cyclopropylmethyloxy-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, (R) -7-chloro-5- (cyclopropylmethoxy) -1,5-dihydro-
3-Ethyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (cyclopropylmethyloxy) -1,5-dihydro-3-ethyl-5 -(Trifluoromethyl) -1,3-benzodiazepine-2
-One, (R) -7-chloro-3-ethyl-5- (3-methyl-2-butenyloxy)
-1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-3-ethyl-5-allylthio-1,5-dihydro-5-
(Trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-3-ethyl-5-cyclobutylmethyloxy-1,5-
Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-3-ethyl-5-cyclopropylmethylthio-1,5-
Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-3-ethyl-5- (1-methylcyclopropyl) methyloxy-1,5-dihydro- 5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-3-propyl-5-cyclopropylmethyloxy-1,
5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-2-
On, (R) -7-fluoro-5- (cyclopropylmethoxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-fluoro- 3-ethyl-5-cyclopropylmethyloxy-1,
5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-2-
ON, (R) -7-fluoro-5- (cyclobutylmethoxy) -1,5-dihydro-
5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-fluoro-3-ethyl-5-cyclobutylmethyloxy-1,5
-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- [2- (1-methylcyclopropyl) ethynyl]-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, (R) -7-chloro-5-cyclobutylmethyloxy-1,5-dihydro-5
-(Trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (3-methyl-2-butenyloxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (phenylmethyloxy) -1,5-dihydro-5
-(Trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5-[(2-pyridyl) methyloxy] -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5-[(1-methylcyclopropyl) methyloxy]-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, (R) -7-chloro-5- (3-methylphenyloxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R)- 7-chloro-5- (cyclopropylmethylthio) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (propylthio)- 1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, and (R) -7-chloro-5- (2-propenylthio) -1,5-dihydro-5-
It is selected from the group of (trifluoromethyl) -1,3-benzodiazepin-2-ones or their pharmaceutically acceptable salt forms.

In another embodiment, the invention provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt form thereof.

In another embodiment, the invention is a novel method of treating HIV infection, wherein a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt form thereof is in need of such treatment. Provided is a novel method of treating HIV infection which comprises administering to a host.

In another embodiment, the present invention is a novel method of treating HIV infection, which comprises an effective amount of (a) a compound of formula I, and (b) an HIV reverse transcriptase inhibitor and an HIV protease inhibitor. There is provided a novel method of treating HIV infection, which comprises administering at least one compound selected from the group in combination to a host in need thereof.

In another preferred embodiment, the reverse transcriptase inhibitor is AZT, ddC, ddI, d
4T, 3TC, DPC082, DPC083, DPC961, DPC963, A
G1549, delavirdine, efavirenz (ef)
avirenz), nevirapine, Ro18893, trovirdine, MKC-442, HBY 097, AC
T, UC-781, UC-782, RD4-2025, and MEN10979.
And a protease inhibitor is saquinavir, ritonavir, indinavir, amprenavir, nelfinavir, parinavir, BMS-232623,
GS3333, KNI-413, KNI-272, LG-71350, CGP-
61755, PD173606, PD177298, PD178390, PD1
78392, U-140690 and ABT-378.

In a further preferred embodiment, the reverse transcriptase inhibitor is AZT, efavire
nz, and 3TC, and the protease inhibitor is selected from the group saquinavir, ritonavir, nelfinavir, and indinavir.

[0051]   In an even more preferred embodiment, the reverse transcriptase inhibitor is AZT.

In another even more preferred embodiment, the protease inhibitor is indinavir.

In another embodiment, the invention is a pharmaceutical kit useful in the treatment of HIV infection, comprising:
From the group consisting of (a) a compound of formula I or a pharmaceutically acceptable salt form thereof, in a therapeutically effective amount in one or more containers, and (b) an HIV reverse transcriptase inhibitor and an HIV protease inhibitor. Provided is a pharmaceutical kit useful in the treatment of HIV infection, which comprises at least one selected compound.

In another embodiment, the present invention provides novel compounds of formula I or their pharmaceutically acceptable salt forms for use in therapy.

In another embodiment, the present invention provides the use of a novel compound of formula I or a pharmaceutically acceptable salt form thereof for the manufacture of a medicament for the treatment of HIV.

Definitions The compounds described herein can have asymmetric centers. The compounds of the invention containing asymmetrically substituted atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms are well known to those skilled in the art, such as by resolution of racemic forms or synthesis from optically active starting materials. Geometric isomers of olefins and double bonds such as C = N double bonds can also be present in the compounds described herein, and all such stable isomers are also contemplated by the present invention. . The cis and trans geometric isomers of the compounds of the present invention have been described and can be isolated as a mixture of isomers or separated isomeric forms. All chiral, diastereomeric, racemic, and geometric isomeric forms of a given structure are contemplated, unless the specific stereochemical form or isomer is specifically indicated. The processes used to prepare compounds of the present invention and the intermediates formed therein are all
It is considered part of the present invention.

As used herein, the term “substituted” refers to any one of the specified atoms, provided that the normal valence of the specified atom is not exceeded and the substitution results in a stable compound. Or, it means that a plurality of hydrogens are replaced with a group selected from the indicated group. When a substituent is keto (ie, = 0), then 2 hydrogens on the atom are replaced. The keto substituent is not present on the aromatic part. When we say that a ring system (eg, carbocycle or heterocycle) is substituted with a carbonyl group or a double bond,
It means that the carbonyl group or double bond of the ring is part of the ring (ie, within the ring).

The present invention is meant to include all isotopes of atoms occurring within the present compounds.
Isotopes include those atoms having the same atomic number but different mass numbers. By way of non-limiting general example, isotopes of hydrogen include tritium and deuterium. Carbon isotopes include C-13 and C-14.

When a variable (eg, R ⁶ ) occurs more than once in any structure or formula of a compound, each occurrence definition is independent of any other occurrence definition.
Thus, for example, if a group is shown to be substituted with 0 to 2 R ⁶ , the group may be optionally substituted with up to 2 R ⁶ groups and at each occurrence R ^{6 of} is independently selected from the definition of R ⁶ . Also, a combination of substituents and / or variables is permissible only if the combination results in a stable compound.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. .
When a substituent is listed without indicating the atom that such substituent is bound to the remainder of the compound of the given formula, then such substituent may be any atom within such substituent. It is possible to connect via. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

As used herein, “alkyl” or “alkenyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C _{1 A-6} alkyl (or _{alkylene), C 1, C 2,} C 3, C 4,
It shall contain C ₅ and C ₆ alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl,
Includes t-butyl, n-pentyl, and s-pentyl. "Haloalkyl"
And are both branched and straight chain saturated aliphatic hydrocarbons having the specified number of carbon atoms and substituted with one or more halogens (eg, v = 1 to 3 and w
= To from 1 intended to include (2v + 1) is -C _v F _w). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. “Alkoxy” refers to an alkyl group, as defined above, of the indicated number of carbon atoms attached through an oxygen bridge. C _{1 ~ 10} alkoxy is intended to include _{C 1, C 2, C 3} , C 4, C 5, C 6, C 7, C 8, C 9, and C ₁₀ alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. “Cycloalkyl” shall include saturated ring groups such as cyclopropyl, cyclobutyl, or cyclopentyl. C _{3 ~ 10} cycloalkyl is intended to include _{C 3, C 4, C 5} , C 6, C 7, C 8, C 9, and C ₁₀ cycloalkyl group. “Alkenyl” or “alkenylene” means either straight or branched chain arrangements, such as ethenyl and propenyl, and one or more unsaturated carbon-carbons which may occur at any stable position along the chain. A hydrocarbon chain composed of a bond and is included. C _{2 ~ 6} alkenyl (or alkenylene) is meant to include _{C 2, C 3, C 4} , C 5, and C ₆ alkenyl groups. “Alkynyl” or “alkynylene” refers to either straight or branched chain arrangements such as ethynyl and propynyl, as well as one or more triple carbons that may occur anywhere along the chain, stable.
A hydrocarbon chain composed of carbon bonds is included. C _{2 ~ 6} alkynyl (or alkynylene) is meant to include _{C 2, C 3, C 4} , C 5, and C ₆ alkynyl groups.

As used herein, “halo” or “halogen” means fluoro, chloro,
Refers to bromo and iodo, and "counterion" is used to represent small negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein, “carbocycle” or “carbocyclic group” refers to any stable 3, 4, 5, 6, or 7 membered monocyclic or bicyclic or 7,8. , 9- or 10-membered bicyclic or tricyclic rings, any of which can be saturated, partially unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0] bicyclooctane, [4.3.0] bicyclononane. , [4.4.0] bicyclodecane, [
2.2.2] Bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.

The term “heterocycle” or “heterocycle group” as used herein refers to saturated,
A partially unsaturated, or unsaturated (aromatic), stable atom consisting of carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, NH, O and S 5-, 6-, or 7-membered monocyclic or bicyclic or 7, 8, 9 or 1
A 0-membered bicyclic heterocycle is meant to include bicyclic groups in which any heterocycle as defined above is fused to a benzene ring. The nitrogen and sulfur heteroatoms can be optionally oxidized. The heterocycle may be attached to any heteroatom or carbon atom with a pendant group that forms a stable structure. The heterocycles described herein may be carbon or nitrogen substituted so long as the resulting compound is stable. The heterocyclic nitrogen can be optionally quaternized. When the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are preferably not adjacent to one another. The total number of S and O atoms in the heterocycle is preferably 1 or less. As used herein, the term "aromatic heterocyclic group" or "heteroaryl" refers to carbon atoms and 1,2,3 independently selected from the group consisting of N, NH, O and S.
, Or a stable 5-, 6-, or 7-membered mono- or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring consisting of 4 or 4 heteroatoms is contemplated. To be done. Note that the total number of S and O atoms in this aromatic heterocycle is 1 or less.

Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, Benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carborinyl, chromanyl, chromenil, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2 , 3-b] Tetrahydrofuran, furanyl, flazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranil , Isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,
Oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrollyri Nyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl,
Pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolidinyl, quinoxalinyl, quinuclidinyl. Tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3
, 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1 , 3,4-triazolyl, and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, 1
Included are H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxyindolyl, benzoxazolinyl, and isatinoyl. Also included are fused rings and spiro compounds containing, for example, the above heterocycles.

As used herein, “HIV reverse transcriptase inhibitor” shall refer to both nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT). Examples of nucleoside RT inhibitors include, but are not limited to, AZT, ddC, d
Includes dI, d4T, and 3TC. Also, Glaxo's AZT and 3
Combinations of TCs are also included. Non-nucleoside RT inhibitors include, but are not limited to, D
PC082 (DuPont, (+)-4-cyclopropylethenyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone), DPC083 (DuPont, (-)-6. -Chloro-4-E-cyclopropylethenyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone), DPC961 (DuPont, (-)-6-chloro-4-cyclopropylethynyl-). 4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone), DPC963 (DuPont, (+)-4-cyclopropylethynyl-5,6-).
Difluoro-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone), AG1549 (Warner Lambert / Shionogi)
, Delavirdine (Pharmacia and Upj)
oh U90152S), efavirenz (Dupont), nevirapine (Boehringer Ingel)
heim), Ro 18,893 (Roche), trovirdin (trovir)
dine) (Lilly), MKC-442 (Triangle), HBY 0
97 (Hoechst), ACT (Korean Research Inst)
it), UC-781 (Rega Institute), UC-782.
(Rega Institute), RD4-2025 (Tosoh Co. L.
td. ), And MEN 10979 (Manarini Farmaceut
ici) is included.

The phrase “pharmaceutically acceptable” as used herein means, within the scope of sound medical judgment, an excess of toxicity, irritation, allergic response, corresponding to a reasonable benefit / risk ratio.
Or used to refer to those compounds, materials, compositions, and / or dosage forms suitable for use in contact with human and animal tissues without causing other problems or complications .

As used herein, “pharmaceutically acceptable salt” refers to a derivative of a disclosed compound that is modified by forming the acid or base salt of the parent compound.
Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines, and alkaline or organic salts of acidic groups such as carboxylic acids. This pharmaceutically acceptable salt includes, for example, the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, and acetic acid, propionic acid, Succinic acid, glycolic acid, stearic acid,
Lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid,
Included are salts prepared from organic acids such as methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts include the free acid or free base form of these compounds in water or in an organic solvent, or in a mixture of the two (typically ether, ethyl acetate, ethanol, isopropanol, or acetonitrile such as Non-aqueous solvents are preferred) and can be prepared by reacting with a stoichiometric amount of a suitable base or acid. Examples of suitable salts are Remington, the disclosure of which is incorporated herein by reference.
'S Pharmaceutical Sciences, 17th Edition, Mack
Publishing Company, Easton, PA, 1985, p.
1418.

Compounds of the invention are delivered in prodrug form because prodrugs are known to enhance many desirable properties of drugs, such as solubility, bioavailability, manufacturability, and the like. It is possible to Accordingly, this invention is intended to cover prodrugs of the compounds of the present claims, methods of delivery thereof and compositions containing the same. “Prodrug” is intended to include covalently bonded carriers which release the active parent drug of the invention in vivo when such prodrug is administered to a mammalian subject. The prodrugs of the present invention are prepared by modifying functional groups present on the compound in such a manner that the modification is cleaved to the parent compound either by conventional manipulations or in vivo. The prodrug, when the prodrug of the present invention is administered to a mammalian subject, a hydroxyl group which is cleaved to form a free amino group, a free amino group, or a free sulfhydryl group, an amino group, or a sulfhydryl group, respectively, Included are compounds of the invention attached to any group. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups of compounds of the invention.

“Stable compound” and “stable structure” refer to a compound that is sufficiently robust to withstand a useful degree of purity from a reaction mixture and to be formulated into an efficacious therapeutic agent. Means that.

A “therapeutically effective amount” is an amount of a compound of the invention or claimed compound that is effective to inhibit HIV infection of a host or to treat the symptoms of HIV infection. The amount of the combination of The combination of compounds is preferably a synergistic combination. Synergism is, for example, “Chou and Talal
ay, Adv. Enzyme Regul. 22: 27-55 (1984) ", the effect of the compounds (in this case, inhibition of HIV) when administered in combination is the addition of the compounds when administered alone as a single agent. It occurs when it exceeds the effect. In general, the synergistic effect is most clearly demonstrated at suboptimal concentrations of compound. Synergy can be seen with respect to reduced cytotoxicity, increased antiviral effect, or some other beneficial combined effect compared to the individual components.

Synthesis The compounds of the present invention can be prepared by a number of methods familiar to one of ordinary skill in the art of organic synthesis. The compounds of the present invention may be combined with synthetic methods known in the field of synthetic organic chemistry, or variations thereof well understood by those skilled in the art,
It can be synthesized using the methods described below. Preferred methods include, but are not limited to, those described below. All references cited below are incorporated herein by reference. In the schemes below, R ¹ is shown as a CF ₃ group, but can be any R ¹ group described herein.

[0074]

[Chemical 11]

Scheme 1 illustrates a method for making a tetrahydroquinolinone intermediate. Acylation of the appropriately substituted amino-ketone and cyclization of the resulting amide in the presence of benzenesulfinate gives alcohol 1c. By dehydration with base, α,
β-Unsaturated ketone 1d is obtained, which is modified with lithium or Grignard reagent to give 2. Sulfone reduction is achieved by Al / Hg or other known reduction methods, leaving intermediate 3.

[0076]

[Chemical 12]

Scheme 2 shows the modification of intermediate 3 to 1,3-benzodiazepin-2-one. Compound 3 is protected with Boc-anhydride as amide 4 and ring opened to hydroxyamide 5. Lossen rearrangement and deprotection is then accomplished by tosyl chloride and with base followed by trifluoroacetic acid to give the desired 1,3-benzodiazepin-2-one 6.

[0078]

[Chemical 13]

Scheme 3 shows a method for reducing acetylene 6 to cis-olefin 7 using NH ₂ OSO ₃ H and DIEA. Other known methods of reducing alkynes to alkenes can also be used. In Scheme 3 and the schemes that follow, G can be R ³ , R ⁴ , R ⁵ , R ⁶ or a combination of two or more of these groups.

[0080]

[Chemical 14]

The thiourea of the present invention can be formed from the corresponding urea as shown in Scheme 4. Urea 6 is first converted to a halo-imine by a chlorinating agent such as POCl ₃ and then further converted to thiourea 8 by NH ₂ C (S) NH ₂ .

Another method of preparing compounds of the present invention is shown in Scheme 5 below and is performed through a nitro-olefin intermediate.

[0083]

[Chemical 15]

Starting with the appropriately substituted ketone 9, the nitromethane is added and the alkoxide 10 is quenched with a protecting group such as TBS-Cl to give the silyl ether 11. Nitro - olefin 12, the base (e.g., K ₂ CO ₃₎ can be formed by heating a 11 in the presence of. R ² (eg, butyl) is
Grignard addition (eg BuMgCl), (R ² ) ₃ Al addition (eg
(Cyclopropylethyl) ₃ Al) or other known methods of addition to nitro-olefins. The change to 14 can be accomplished by reducing the nitro group to an amino group, deprotecting the aniline amine and finally cyclizing with a carbonyl reagent such as CDI.

[0085]

[Chemical 16]

Another means of preparing the compounds of this invention is depicted in Scheme 6. Treatment of trifluoromethyl ketone with diazomethane, dimethylsulfonium methylide, or dimethylsulfoxonium methylide gives the epoxide. The epoxide is then reacted with a primary amine to give the ring-opened alcohol, which is treated with N, N'-carbonyldiimidazole to give a mixture of 5- and 7-membered ring amides. This mixture was treated with sodium methoxide or triethylamine in ethanol,
This is converted to the desired 7-membered ring urea. In addition to N, N'-carbonyldiimidazole, phosgene, triphosgene, methyl chloroformate or some similar reagents well known to those skilled in the art can also achieve the conversion to cyclic ureas. By treating the cyclic urea with thionyl chloride, chlorides, i.e. R ₂ substituted compound when treated with lithium reagent or Grignard reagent (R ² = alkyl, aryl, alkynyl or alkenyl) compound providing is obtained. Reaction of this chloride with amines, alkoxides, or thioalkoxides yields QR-substituted compounds (Q = O, S, NH). For the synthesis of compounds of the invention where R ⁸ = H, it is preferred to cleave the epoxide with an amine (R ⁸ NH ₂ ) whose alkyl group (R ⁸ ) can be removed during the final synthetic steps. Some such removable alkyl groups are well known to those skilled in the art, preferred examples of which are:
Allyl, p-methoxybenzyl (PMB) and 2,4-dimethoxybenzyl (
DMB). Allyl groups can be removed by treatment with rhodium chloride followed by aqueous acid. PMB and DMB groups can be removed by catalytic hydrogenation, reaction with a strong acid such as trifluoroacetic acid, or treatment with an oxidizing agent such as cerium ammonium nitrate, DDQ, or sodium persulfate.

[0087]

[Chemical 17]

Scheme 7 describes a means of obtaining amino-ketones useful in the above schemes. After iodination of the appropriate aniline, a strong base and ethyl trifluoroacetate can be used to introduce the trifluoromethyl group.

[0089]

[Chemical 18]

Certain benzo-substituents are not suitable for the methods of the above schemes, so it may be necessary to protect these groups before forming the desired product. Scheme 8
Shows a means to obtain carbonyl-substituted iodo-anilines that can be modified as shown in Scheme 7. After iodination of acetyl-aniline, the acetyl group was converted to 1,3-
Protect by means well known to those skilled in the art such as using propanedithiol. Deprotection of the ketone can then be accomplished using HgCl ₂ and HgO or other methods familiar to those skilled in the art.

[0091]

[Chemical 19]

In addition to the method for obtaining keto-aniline described above, nucleophilic ring opening of isatoic anhydride can also be used as shown in Scheme 9. This reaction can be accomplished using an anionic nucleophile of the R ^1a group. "Mack et al, J. Hete
rocyclic Chem. 1987, 24, 1733-1739 "," Co
ppola et al. Org. Chem. 1976, 41 (6), 82
5-831 "," Takimoto et al, Fukuoka Univ.
Sci. Reports 1985, 15 (1), 37-38 "," Kadin
et al, Synthesis 1977, 500-501 "," Stai.
ger et al. Org. Chem. 1959, 24, 1214-12
19 ".

[0093]

[Chemical 20]

The 1,3-benzoxazepinones of the present invention can be synthesized as described in Scheme 10. The starting epoxide can be opened with an alkoxide (NaOR ', or KOR'). Here, R'is a protecting group that can be removed at a later stage of the synthesis. There are many such removable groups known to those skilled in the art. These include allyl groups, as well as 2-trimethylsilylethyl or 2,2,2-
A substituted ethyl group such as trichloroethyl, or 3,4-dimethoxybenzyl,
Included are p-nitrobenzyl, and substituted benzyl groups such as diphenylmethyl. The next step is to protect the tertiary alcohol with a second protecting group (R ″) which is stable under the conditions of removal of the first protecting group (R ′). It may be one of a substituted ethyl or substituted benzyl group or a silyl group (such as triethylsilyl, t-butyldimethylsilyl, or t-butyldiphenylsilyl). There are many possible combinations of the two selectively removable protecting groups provided: removal of the first protecting group to give the primary alcohol, which is
Treatment with N'-carbonyldiimidazole or phosgene followed by removal of the second protecting group gives the cyclic carbamate. The cyclic carbamate is treated with thionyl chloride to convert the tertiary alcohol to chloride. Treatment of this compound with a lithium or Grignard reagent provides an R ² substituted compound (R ² = alkyl, aryl, alkynyl, or alkenyl). QR-substituted compounds (Q = O, S, NH) by reaction of chlorides with amines, alkoxides, or thioalkoxides.
To get Additionally, compounds of the invention where Q = O can also be prepared by direct alkylation of tertiary alcohols.

One enantiomer of the compound of formula I may exhibit superior activity as compared to the other. Therefore, the following stereochemistry is considered to be part of the scope of this invention.

[0096]

[Chemical 21]

If necessary, separation of racemates is accomplished by HPLC using a chiral column as illustrated in Examples 27-34 (Scheme 4), or by “Thoma.
sJ. Tucker, et al. Med. Chem. 1994, 37,
2437 to 2444 ”, such as camphoric chloride (camphonic c
This is achieved by resolving using a resolving agent such as hlride).
Chiral compounds of formula I are also described, for example, in “Mark A. Huffman, et.
al, J. Org. Chem. 1995, 60, 1590-1594 ", and can be directly synthesized using a chiral catalyst or a chiral ligand.

Other features of the invention will be apparent in the following exemplary embodiments. This example is provided by way of illustration of the invention and is not intended to be limiting.

EXAMPLES The abbreviations used in the examples are defined below. “° C.” is Celsius, “d” is doublet, “dd” is doublet doublet, “eq” is equivalent or equivalent (s), “g” is gram or gram (s), “mg” Is a milligram or milligrams,
"ML" is milliliter or milliliters, "H" is hydrogen or hydrogen (s), "hr" is hours or hours, "m" is multiline, "M" is moles, "min" is Minutes or minutes, "MHz" for megahertz, "MS" for mass spectrometry, "nmr" or "NMR" for nuclear magnetic resonance spectra, "t" for triplet,
"TLC" is thin layer chromatography, "ACN" is acetic anhydride, "CDI" is carbonyldiimidazole, "DIEA" is diisopropylethylamine, and "DI".
"PEA" is diisopropylethylamine, "DMAP" is dimethylaminopyridine, "DME" is dimethoxyethane, "EDAC" is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and "LAH" is lithium aluminum hydride. , "TBAF" is tetrabutylammonium fluoride, "TBS-"
"Cl" is t-butyldimethylsilyl chloride and "TEA" is triethylamine.

Example 1 7-Chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-5-
Preparation of (trifluoromethyl) -1,3-benzodiazepin-2-one

[0101]

[Chemical formula 22]

Amino ketone 1a (3.02 g, 13.54 m) dissolved in THF (55 mL)
mol) solution at room temperature in potassium carbonate (4.67 g, 33.85 mmol),
Bromoacetyl bromide (1.5 mL, 16.93 mmol) was then added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 100 mL). The combined ethyl acetate extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum to give a yellow oil 1b. This product was used in the next step of the synthetic route without further purification.

Bromide 1b (crude product, 13.54 mmol) dissolved in DMF (55 mL)
Solution of sodium benzenesulfinate (4.44 g, 27.08 m) at room temperature.
mol) was added and the resulting reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 100 mL). The combined ethyl acetate extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. Lump the hexane (1
L) and dried under vacuum to give 4.88 g (theoretical 5.49 g, 89%) of an off-white solid 1c. ¹ HNMR (300 MHz, DMSO-d ₆ ) δ
11.0 (br s, 1H), 7.96 (s, 1H), 7.76 (d, 2H, J
= 8 Hz), 7.66 (m, 1H), 7.51 (m, 2H), 7.44 (s, 1
H), 7.33 (m, 1H), 6.82 (d, 1H, J = 8Hz), 4.47 (
s, 1H). ¹⁹ FNMR (282 MHz, DMSO-d ₆ ) δ-80.99 (s
3F). High resolution mass spectrometry: Calculated value of C ₁₆ H ₁₁ NO ₄ F ₃ ClS (M + H) +:
405.0042, found 405.0049.

A slurry of tertiary alcohol 1c (6.815) in methylene chloride (100 mL).
g, 16.83 mmol) at room temperature with 4- (dimethylamino) pyridine (4.11).
g, 33.65 mmol) followed by acetic anhydride (3.5 mL, 37.03 mmol)
Was added and the resulting reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 100 mL). The ethyl acetate extract was washed with saturated NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The mass was triturated with hexane (1 L) and dried under vacuum to give an off-white solid 1d 6.06 g.
(93%) was obtained. Elemental _{analysis: (C 16 H 9 NO 3} F 3 ClS) Calculated: C49.5
6, H2.35, N3.61, Cl9.14, F14.70, S8.28. Found: C49.26, H2.68, N3.30, Cl9.23, F14.49, S.
8.13.

Cyclopropylacetylene (purity 48%, 14%, dissolved in THF (95 mL)
． To a solution of 6 mL, 80.9 mmol) at 0 ° C. was injected hexane 1.6 M BuLi hexane solution (46 mL, 73.5 mmol). The reaction is carried out at 0 ° C for 15 ~
After stirring for 30 minutes, 1 (9.5 g, 24.5 mmol) was added as a solid and stirred for 2 hours. The reaction was quenched with saturated NH ₄ Cl. The reaction was partitioned between EtOAc and sat. NH ₄ Cl, washed with brine, dried (Na ₂ SO ₄ ) and evaporated to give a solid. White solid 2 (6.6 g, 60% yield) was obtained by flash chromatography (50% EtOAc / hexane).

2 (6.6 g, 14.5 mmol), THF (90 mL) and water (10 mL)
The mixture of Al / Hg in) was refluxed for 1 hour. The reaction was filtered through Celite, partitioned between EtOAc and water, washed with brine, dried (Na ₂ SO ₄ ),
Evaporation gave solid 3 (4 g, 90% yield). MH ⁺ = 314.0559.

3 (4 g, 12.8 mmol) in ACN (60 mL), (Boc) ₂ O (3
． A solution of 06 g, 14 mmol) and DMAP (1.56 g, 12.8 mmol) was stirred for 1 hour. TLC suggested that the ratio of desired product to starting material was about 3: 2. Furthermore, (Boc) ₂ O (0.6 g, 2
． 8 mmol) was added and the reaction was stirred for 10 minutes. TLC showed traces of starting material. The reaction was partitioned between EtOAc and 1N HCl, water,
Washed with saturated NaHCO ₃ and brine, dried (Na ₂ SO ₄ ) and evaporated to give an orange solid 4 (4.93 g, 93% yield).

4 (4.63 g, 11.2 mmol) in EtOH (65 mL), H ₂ NOH
HCl (3.11 g, 44.8 mmol) and DIEA (7.8 mL, 44
． 8 mmol) was stirred for 2 hours. The reaction was diluted with EtOAc and washed with dilute HCl (6X), water, saturated NaHCO ₃ , brine, dried (Na ₂ SO ₄ ) and evaporated to a thick orange oil 5 ( 5.3 g, yield 95%)
Got

5 (4.94 g, 11 mmol) in dioxane (240 mL), TsCl (
5.32 g, 27.9 mmol) and 1 N NaOH (53.2 mL, 53.2).
(mmol) solution was stirred for 1.5 hours. The reaction was diluted with EtOAc and sat.
Partitioned into aHCO ₃ , washed with brine and evaporated to give a semi-solid. TFA (
A semi-solid solution of 20 mL) and CH ₂ Cl ₂ (200 mL) was stirred for 2 hours and evaporated to give a thick oil. This oil was partitioned between EtOAc and saturated NaHCO ₃ and brine, dried (Na ₂ SO _4), to give an oil of thick dark orange evaporated. Crystallization from dichloroethane gave a white crystalline solid 6 (1.2
5 g, yield 40%, mp 240-242 ° C) was obtained.

Example 2 Preparation of 6,7-difluoro-5- (2-cyclopropylethynyl) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0111]

[Chemical formula 23]

The 6,7-DiF analog 6a was prepared using a route similar to Example 1, but starting from the difluoro analog 1a. mp = 232-233 ° C.

Example 3 7-Chloro-5- (2-cyclopropylethenyl) -1,5-dihydro-5-
Preparation of (trifluoromethyl) -1,3-benzodiazepin-2-one

[0114]

[Chemical formula 24]

6 (60 mg), NH ₂ OSO ₃ H (1.5 g) and D in THF (5 mL)
A suspension of IEA (3 mL) was refluxed for 48 hours. The reaction was diluted with EtOAc, washed with 1N HCl (2X), water, brine, dried (Na ₂ SO ₄ ) and evaporated to give a solid, crystallized from dichloroethane to give white crystals. Solid 7 (
30 mg, mp221-223 ° C) was obtained.

Example 4 7-Chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-5-
Preparation of (trifluoromethyl) -1,3-benzodiazepine-2-thione

[0117]

[Chemical 25]

A suspension of 6 (50 mg) and Na ₂ CO ₃ (24 mg) in POCl ₃ (1 mL) was heated at 95 ° C. for 24 hours and evaporated to give a semi-solid. This solid and NH ₂ CSNH ₂ (63 mg) were refluxed in EtOH (4 mL) over the weekend. The reaction was diluted with EtOAc, washed with water and brine and dried (N
a ₂ SO ₄ ) and evaporated to give a solid. Flash chromatography (25
~ 50% EtOAc / Hexane) gave a white solid (22 mg). Crystallization from dichloroethane gave a white crystalline solid 8 (13 mg, mp 230 ° C decomposed).

Example 5 Preparation of 7-chloro-5- (2-n-butyl) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0120]

[Chemical formula 26]

To a solution of 9 (8.48 g, 18.2 mmol) and nitromethane (1.97 mL, 36.4 mmol) in DME (85 mL) was added 60% NaH (2.55 g).
, 63.8 mmol) was added. After stirring for 1.5 hours, TLC showed the ratio of alcohol intermediate 10 to starting material was about 2: 3. T
BS-Cl (13.7 g, 91 mmol) was added and the reaction was stirred for 0.5 h. TLC showed the desired product 11 to 10 ratio was about 4: 1. The reaction was stirred for an additional 2 hours. This reaction product is EtOA
It was diluted with c and partitioned between EtOAc and saturated NaHCO ₃ . The reaction was filtered and the organic layer was washed with brine, dried (Na ₂ SO ₄ ) and evaporated to give an orange oil (22.3g). The oil was triturated with hexane and washed twice with the same solvent to give a yellow solid 11 (8.2 g, yield 75%).

11 (8.2 g, 13.8 mmol) and K ₂ C in toluene (80 mL)
A mixture of O ₃ (2.2 g) was refluxed for 0.5 hours. The reaction was diluted with EtOAc, washed with water, brine, dried (Na ₂ SO ₄ ) and evaporated to give a dark orange oil (7.4g). The oil was triturated with hot hexane and 2 times with the same solvent.
It was washed twice to give a brown solid 12 (5 g, yield 71.5%).

To a solution of 12 (204 mg, 0.4 mmol) in THF (2 mL) was added -78.
Addition of 2M BuMgCl in ether (0.6 mL, 1.2 mmol) at 0 ° C. showed no starting material by TLC. This reaction was saturated NH ₄ Cl
Stop with, partition between EtOAc and sat. NH ₄ Cl, wash with brine and dry (N.
a ₂ SO ₄ ) and evaporated to give an orange oil (240 mg). Flash chromatography (3% EtOAc / Hexanes) gave a pale yellow glass 13 (94 mg).

A slurry of 13 (75 mg), Raney nickel (2 mg) in ethanol (4 mL).
mL) and hydrazine monohydrate (0.1 mL) was stirred for 2 hours. The reaction was filtered through Celite, partitioned between EtOAc and water and brine,
Dry (Na ₂ SO ₄ ) and evaporate to give an orange oil (85 mg). Flash chromatography (20% EtOAc / hexane) gave a pale yellow glass (46 mg). MeOH (1 mL) and concentrated hydrochloric acid (0.1 m
A solution of this glass (46 mg) in L) was stirred for 15 minutes and filtered. The filtrate was partitioned between EtOAc and 1N NaOH and brine, dried (Na ₂ SO ₄ ) and evaporated to give an orange oil (20mg). A solution of this oil (20 mg) and carbonyldiimidazole (33 mg) in THF (1 ml) was stirred overnight. Evaporation of solvent gave an oil, which was Et ₂ O / hexane /
Trituration with CH ₂ Cl ₂ gave 14 as a fine powder (5.6 mg, mp 174-176 ° C).

Another means of converting 12 to 13 is as follows. To a solution of 12 (100 mg, 0.2 mmol) in toluene (2 mL) at −78 ° C. was added 1M (i-Bu) ₃ Al in toluene (0.4 mL, 0.4 mmol), TL
No starting material was observed by C. The reaction was quenched with HCl 0.1M, partitioned between EtOAc and 0.1M HCl, washed with brine and dried (Na ₂ S).
O ₄ ) and evaporated to give an orange oil 13 (121 mg).

Example 6 7-Chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-3-
Preparation of methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0127]

[Chemical 27]

A solution of about 15 mmol of diazomethane in 40 mL of ether was sold by the vendor (Al
Produced from 5 g of Diazald® according to the instructions provided by the Drich Chemical Company). This solution was mixed with 10 m of ether.
To a solution of 201 (2.6 g, 11.6 mmol) in L was added and the reaction mixture was stirred at room temperature for 3 hours. At this point it was shown that the tlc had fully converted to the epoxide 202. Excess diazomethane was quenched by the addition of acetic acid, 10 mL of ethanol was added and the solution was concentrated on a rotary evaporator to a volume of about 10 mL. To this solution was added 20 mL of 33% methylamine ethanol solution and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give a semi-solid product 203 (3.4 g) which was used in the next reaction without purification.

To a solution of 203 (2.9 g, 10.8 mmol) in 50 mL dry THF was added N 2.
, N′-Carbonyldiimidazole (2.6 g, 16.2 mmol) was added and the reaction mixture was stirred at ambient temperature for 1.75 h. An additional 500 mg of N, N'-carbonyldiimidazole was added and the reaction was allowed to proceed for another 30 minutes.
Sodium methoxide in methanol (10 mL of a 3.24 M solution) was added and the mixture was refluxed for 30 minutes. The cooled mixture was poured into aqueous ammonium chloride solution and the mixture was extracted twice with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated to an orange oil. Flash chromatography (50-70% EtOAc / hexane) after washing with methylene chloride gave white solid 204 (1.5 g, 42.5% yield).

To a solution of 204 (1.17 g, 3.97 mmol) in 50 mL dry THF,
Triethylamine (2.3 mL, 16.67 mmol) and thionyl chloride (1
． 2 mL, 15.88 mmol) was added. After stirring for 15 minutes at ambient temperature,
25 mL of methanol was added and the mixture was stirred for 15 minutes before pouring the mixture into aqueous sodium bicarbonate solution. The mixture was extracted with ether, the extract was dried over magnesium sulfate, concentrated to a yellow solid 205 (1.18 g, 95% yield) and used without purification.

Cyclopropylacetylene (35% pure, 0.45 mL) in THF (3 mL)
) Solution of 1.6 M BuLi in hexane (0.625 mL, 1.0 mm
ol) was injected at 0 ° C. The reaction mixture was stirred at 0 ° C. for 30 minutes and then the reaction mixture was cooled to −
Cool to 50 ° C. and remove 205 (85 mg, 0.27 m) in THF (0.7 mL).
mol) was added and the reaction mixture was allowed to warm to room temperature over 2 hours. The reaction was poured into saturated ammonium chloride and extracted with ether. The extract was washed with brine, dried over magnesium sulfate and evaporated to give an oil. Flash chromatography (50%, EtOAc / hexane) followed by crystallization with ethyl acetate / hexane gave colorless crystals of the title compound (27 mg, mp 177-178 ° C).

Example 7 7-Chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-3-
Preparation of ethyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0133]

[Chemical 28]

The title compound (mp 186-188 ° C) was prepared according to the method of Example 6 substituting ethylamine for methylamine.

Example 8 7-Chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-3-
Cyclopropyl-5- (trifluoromethyl) -1,3-benzodiazepine-2
-Preparation of ON

[0136]

[Chemical 29]

The title compound (mp 195-196 ° C) was prepared according to the method of Example 6 substituting cyclopropylamine for methylamine.

Example 9 Preparation of 7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0139]

[Chemical 30]

Cyclopropylcarbinol (250 mg, 3.5 mm in 5 ml dry THF
ol) was added sodium hydride (50 mg, 2.1 mmol) at room temperature. After 30 minutes, 205 (150 mg, 0.48 mmol) was added and the reaction mixture was stirred for 30 minutes at ambient temperature. The reaction was poured into saturated ammonium chloride and extracted with ether. The extract was washed with brine, dried over magnesium sulfate and evaporated to give an oil. Flash chromatography (50% EtO
Ac / Hexane) gave 49 mg of a solid, which was recrystallized from ethyl acetate / hexane to give the title compound (20 mg, mp 192-193 ° C.) as colorless crystals.

Example 10 7-Chloro-5- (3-methyl-2-butenyloxy) -1,5-dihydro-
Preparation of 3-methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0142]

[Chemical 31]

3-Methyl-2-buten-1-ol (310 mg, 3 in 3 mL of dry THF
． 6 mmol) in a solution of sodium hydride (80 mg, 3.33 mmo at room temperature).
l) was added. After 30 minutes, 205 (160 mg, 0.51 mmol) was added and the reaction mixture was stirred at ambient temperature for 30 minutes. The reaction was poured into saturated ammonium chloride and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated to give an oil. Flash chromatography (
90 mg solid was obtained with 30-50% EtOAc / hexane) and recrystallized with ethyl acetate / hexane to give colorless crystals of the title compound (mp 181-282 ° C.).

Example 11 7-Chloro-5- (3-allyloxy) -1,5-dihydro-3-methyl-5
Preparation of-(trifluoromethyl) -1,3-benzodiazepin-2-one

[0145]

[Chemical 32]

To a solution of allyl alcohol (243 mL, 3.57 mmol) in 5 mL dry THF was added sodium hydride (82 mg, 3.41 mmol) at room temperature.
After 30 minutes, 205 (160 mg, 0.51 mmol) in THF (3 mL) was added and the reaction mixture was stirred at ambient temperature for 35 minutes. The reaction was poured into saturated ammonium chloride and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated to give an oil. Flash chromatography (40-60% EtOAc / hexane) gave 99 mg of a solid which was recrystallized with ethyl acetate / hexane to give colorless crystals of the title compound (mp 163-165 ° C).

Example 12 7-Chloro-5- (3,3-dichloro-2-propenyloxy) -1,5-dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepine-2 -Preparation of ON

[0148]

[Chemical 33]

The title compound (mp 148.6-149.9 ° C.) was prepared according to the method of Example 11.
Prepared by substituting 3,3-dichloro-2-propenol for allyl alcohol.

Example 13 Preparation of 7-chloro-5- (2-propynyloxy) -1,5-dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0151]

[Chemical 34]

The title compound (mp229.7-232.1 ° C) was prepared according to the method of Example 11.
Prepared by substituting 2-propyn-1-ol for allyl alcohol.

Example 14 7-Chloro-5- (2-fluoro-6-methoxybenzyloxy) -1,5-
Preparation of dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0154]

[Chemical 35]

The title compound (mp 172.1-173.8 ° C.) was prepared according to the method of Example 11.
Prepared by substituting 2-fluoro-6-methoxybenzyl alcohol for allyl alcohol.

Example 15 7-Chloro-5- (cyclopropylmethyloxy) -1,5-dihydro-5
Preparation of (trifluoromethyl) -1,3-benzodiazepin-2-one

[0157]

[Chemical 36]

To a solid mixture of 95% sodium hydride (650 mg, 25.7 mmol) and trimethylsulfoxonium iodide (6.0 g, 27 mmol) was added dry DM.
35 mL of SO was added dropwise with stirring over 15 minutes. After stirring at ambient temperature for an additional 20 minutes, the evolution of hydrogen ceased and 201 (3.3
A solution of 5 g, 15 mmol) was poured over 3 minutes. After another 2 minutes, the reaction was quenched with water. The reaction mixture was poured into water and extracted with ether. The ether layer was washed twice with brine and dried over magnesium sulfate. Ethanol (15 mL
) Was added to the ether solution and it was concentrated under reduced pressure at 20 ° C. to a volume of 15 mL. Allylamine (4.6 g, 81 mmol) was added and the solution was stirred overnight at ambient temperature before it was concentrated at 40 ° C. to give 206 as an oily product.
Got

To a solution of 206 in 65 mL dry THF was added N, N′-carbonyldiimidazole (2.5 g, 15 mmol) and triethylamine (6.3 mL, 45 mm).
ol) was added and the reaction mixture was stirred overnight at ambient temperature. Ethanol (2
5 mL) was added and the mixture was refluxed for 2 hours then evaporated to small volume.
This was taken up in ethyl acetate and this solution was washed with water, aqueous citric acid solution and brine, dried over sodium sulfate and concentrated to an oil. Methylene chloride was added to precipitate the product and 207 was collected as colorless crystals (3.05 g, 63%).

To a solution of 207 (4.6 g, 14.38 mmol) and pyridine (1.393 mL, 17.25 mmol) in 55 mL dry THF at 0 ° C. thionyl chloride (
1.865 g, 15.8 mmol) was added dropwise. After the addition was complete, the cooling bath was removed and stirring continued at ambient temperature for 1 hour. The reaction mixture was partitioned between water and ethyl acetate and the organic layer was washed with brine, dried and evaporated to give 20 crystalline product.
8 (4.4 g) was obtained.

To a solution of cyclopropylmethanol (9 mL) in 45 mL dry DMSO was added 1
00% Sodium hydride (1.8 g) was added. This was stirred at ambient temperature for 3 hours until hydrogen evolution ceased, after which 208 (4.4 g, 13 mmol) was added in one portion. After stirring for 1 hour at ambient temperature, the reaction mixture was partitioned between ethyl acetate and aqueous citric acid solution, the organic layer was washed with brine, dried (sodium sulfate) and evaporated to give an oily product. Flash chromatography (25% EtOAc /
Hexane) and after crystallization with hexane, 209 (3.0 g) was obtained.

A solution of 209 (1.2 g) and rhodium trichloride hydrate (60 mg) in ethanol (100 mL) was refluxed for 2 hours. Cool the mixture to 60 ° C. and
N hydrochloric acid (20 mL) was added and the mixture was stirred at 60 ° C. for 2 hours. The cooled mixture was partitioned between water and ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate solution and brine, dried and evaporated to give a solid. Flash chromatography (50-75% ether / hexane) followed by crystallization from methylene chloride-hexane to give the title compound as colorless crystals (840 mg, 78%, mp 185-18).
6 ° C.) was obtained.

Example 16 Preparation of (S) -7-chloro-5- (cyclopropylmethyloxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0164]

[Chemical 37]

Racemic 7-chloro-5- (cyclopropylmethyloxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one (1.
2 g) is a Chiralcel-OD-AMB liquid chromatography column (
It is separated into its enantiomeric constituents with 10% EtOH-hexane). The previously eluted enantiomer was crystallized from ethyl acetate-hexane to give the title compound (3
35 mg, mp 190-191 ° C.) was obtained, and the absolute configuration (S) was determined.

Example 17 7-Chloro-3-cyclopropyl-5- (cyclopropylmethoxy) -1,5
-Preparation of dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0167]

[Chemical 38]

To a solid mixture of 95% sodium hydride (1.94 g, 81 mmol) and trimethylsulfoxonium iodide (17.8 g, 81 mmol) was added dry DMS.
100 mL of O was added dropwise over 20 minutes while stirring. After stirring for a further 20 minutes at ambient temperature, the evolution of hydrogen ceased and 201 (10 g of dry THF (200 mL) was added.
, 44.7 mmol) was injected over 5 minutes. After a further 2 minutes, the reaction was quenched with water. The reaction mixture was poured into water and extracted with ether. The ether layer was washed twice with brine and dried over magnesium sulfate. Ethanol (35 mL) was added to the ether solution and it was concentrated under reduced pressure at 20 ° C. to a volume of 35 mL. Cyclopropylamine (12.4 mL, 179 mmol) was added,
The solution was stirred overnight at ambient temperature and then at 50 ° C. for 2 hours, then concentrated at 40 ° C. to give 210 (9.4 g) as an oily product.

To a solution of 210 (9.4 g, 31.9 mmol) in 250 mL dry THF,
N, N'-Carbonyldiimidazole (9.3 g, 57.4 mmol) was added and the reaction mixture was stirred overnight at ambient temperature and evaporated to give a solid. ethanol(
150 mL) and triethylamine (13 mL) were added and the mixture was refluxed for 4 hours then evaporated to a small volume. This is taken up in ethyl acetate, this solution is taken up with water,
It was washed with aqueous citric acid solution and brine, dried over sodium sulfate and concentrated to an oil. Crystallization from ethyl acetate-hexane gave 2.6 g of a crystalline product. Flash chromatography on silica gel (40-50% ethyl acetate-hexane) of the mother liquor gave an additional 1.7 g, giving a total of 4.3 g (42%) of 211 as colorless crystals.

A solution of 211 (4.3 g, 13.4 mmol) and pyridine (1.6 mL, 20.1 mmol) in 48 mL dry THF was added to thionyl chloride (2.0 m) at 0 ° C.
L) was added dropwise. After the addition was complete, the cooling bath was removed and stirring continued at ambient temperature for 20 minutes. The reaction mixture was partitioned between water and ethyl acetate and the organic layer was washed with brine, dried and evaporated to give 212 (4.2g) as a crystalline product.

To a solution of cyclopropylmethanol (9 mL) in 75 mL dry DMSO, 1
00% Sodium hydride (840 mg) was added. This was stirred at ambient temperature for 1 hour until hydrogen evolution ceased, and 212 (4.0 g, in DMSO (25 mL) was added.
11.8 mmol) was added. After stirring for 1 hour at ambient temperature, the reaction mixture was partitioned between ethyl acetate and aqueous citric acid solution, the organic layer was washed with brine, dried (magnesium sulfate) and evaporated to give an oily product. After flash chromatography on silica gel (10-60% EtOAc-hexane) and crystallization with ethyl acetate-hexane, the title compound (2.15 g, 49%, mp 153.5-15).
5 ° C.) was obtained as colorless crystals.

Example 18 (S) -7-Chloro-3-cyclopropyl-5- (cyclopropylmethoxy)
Preparation of -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0173]

[Chemical Formula 39]

Racemic 7-chloro-3-cyclopropyl-5- (cyclopropylmethoxy)
-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one is a chiralcel OD-H liquid chromatography column (
Separation into its enantiomeric constituents with 10% EtOH-supercritical carbon dioxide). The previously eluted ethane thiomer was crystallized from hexane to give the title compound (320 mg
, Mp 66-68 ° C.) was obtained. This was assigned the absolute configuration (S).

Example 19 7-Chloro-3-cyclopropyl-5-propyloxy-1,5-dihydro-
Preparation of 5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0176]

[Chemical 40]

The title compound (mp 153-154 ° C.) was prepared according to the method of Example 17 substituting propanol for cyclopropylmethanol.

Example 20 7-Chloro-3-cyclopropyl-5-propylthio-1,5-dihydro-5
Preparation of-(trifluoromethyl) -1,3-benzodiazepin-2-one

[0179]

[Chemical 41]

The title compound (mp 150-151 ° C) was prepared according to the method of Example 17, substituting propanethiol for cyclopropylmethanol.

Example 21 7-Chloro-3-cyclopropyl-5-allylthio-1,5-dihydro-5-
Preparation of (trifluoromethyl) -1,3-benzodiazepin-2-one

[0182]

[Chemical 42]

The title compound (mp 144-145.5 ° C.) was prepared according to the method of Example 17 substituting allyl mercaptan for cyclopropylmethanol.

Example 22 7-Chloro-3-cyclopropyl-5-allyloxy-1,5-dihydro-5
Preparation of-(trifluoromethyl) -1,3-benzodiazepin-2-one

[0185]

[Chemical 43]

The title compound (mp 120-121 ° C) was prepared according to the method of Example 17, substituting allyl alcohol for cyclopropylmethanol.

Example 23 7-Chloro-3-cyclopropyl-5- (3-methyl-2-butenyloxy)
Preparation of -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0188]

[Chemical 44]

The title compound (mp 130-131 ° C) was prepared according to the method of Example 17 substituting 3-methyl-2-butenol for cyclopropylmethanol.

Example 24 7-Chloro-3-cyclopropyl-5-cyclobutylmethyloxy-1,5-
Preparation of dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0191]

[Chemical formula 45]

The title compound (mp 158-159 ° C) was prepared according to the method of Example 17 substituting cyclobutylmethanol for cyclopropylmethanol.

Example 25 7-Chloro-3-cyclopropyl-5- (1-methylcyclopropyl) methyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one Preparation of

[0194]

[Chemical formula 46]

The title compound (mp 166-167 ° C) was prepared according to the method of Example 17 substituting (1-methylcyclopropyl) methanol for cyclopropylmethanol.

Example 26 7-Chloro-3-cyclopropyl-5- (2-pyridyl) methyloxy-1,
5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-2-
On preparation

[0197]

[Chemical 47]

The title compound (mp 170-171.5 ° C) was prepared according to the method of Example 17 substituting 2- (hydroxymethyl) pyridine for cyclopropylmethanol.

Example 27 7-Chloro-3-isopropyl-5-cyclopropylmethyloxy-1,5-
Preparation of dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0200]

[Chemical 48]

The title compound (mp 169.5-170.5 ° C) was prepared according to the method of Example 17 substituting isopropylamine for cyclopropylamine.

Example 28 7-Chloro-3-cyclobutyl-5-cyclopropylmethyloxy-1,5-
Preparation of dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0203]

[Chemical 49]

The title compound (mp 156 ° C.) was prepared according to the method of Example 17 substituting cyclobutylamine for cyclopropylamine.

Example 29 Preparation of 7-chloro-5- (cyclopropylmethoxy) -1,5-dihydro-3-ethyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0206]

[Chemical 50]

A solution of about 28 mmol of diazomethane in 100 mL of ether was sold by the vendor (Al
Produced from 10 g of Diazald® according to the instructions provided by the Drich Chemical Company. This solution was added to ether 2
A solution of 201 (5.2 g, 23.2 mmol) in 0 mL was added and the mixture was stirred at room temperature for 3 hours. At this time, it was confirmed that tlc completely converted to epoxide 202. Excess diazomethane was quenched by the addition of acetic acid, 20 mL of ethanol was added and the solution was concentrated on a rotary evaporator to a volume of about 20 mL. To this solution was added 20 mL of 2M ethylamine in THF and the mixture was stirred in a stoppered flask at 50 ° C. for 5 hours. Evaporate the solvent under reduced pressure and flash chromatography on silica gel (20% ethyl acetate-
After purification with hexane) 213 (2.7 g) was obtained as an oil.

To a solution of 213 (2.7 g) in 45 mL dry THF was added N, N′-carbonyldiimidazole (1.8 g) and triethylamine (4.2 mL) and the reaction mixture was left at ambient temperature overnight. It was stirred. Ethanol (15 mL) was added and the reaction mixture was refluxed for 3 hours then evaporated to small volume. This was taken up in ethyl acetate and this solution was washed with water, aqueous citric acid solution and brine, dried over sodium sulfate and concentrated to an oil. Methylene chloride was added to precipitate the product and 214 was collected as colorless crystals (1.73 g).

214 (1.54 g) and pyridine (0.50 mL in 20 mL dry THF)
Thionyl chloride (0.400 mL) was added dropwise to the solution of (1) at 0 ° C. After the addition is complete
The cooling bath was removed and stirring at ambient temperature was continued for 1 hour. The reaction mixture was partitioned between water and ethyl acetate and the organic layer containing both dissolved and undissolved product was evaporated to give 215 as a crystalline product (1.43g).

To a solution of cyclopropylmethanol (0.20 mL) in 3 mL dry DMSO was added 100% sodium hydride (36 mg). This was stirred at ambient temperature for 30 minutes until hydrogen evolution ceased, then 215 (150 mg) was added in one portion. After stirring for 20 minutes at ambient temperature, the reaction mixture was partitioned between ethyl acetate and aqueous citric acid solution, the organic layer was washed with brine, dried (sodium sulfate) and evaporated to give a solid product. This was recrystallized from ethyl acetate-hexane to give the title compound (85 mg, mp 157 to 159 ° C) as colorless crystals.

Example 30 (S) -7-Chloro-5- (cyclopropylmethyloxy) -1,5-dihydro-3-ethyl-5- (trifluoromethyl) -1,3-benzodiazepine-2
-Preparation of ON

[0212]

[Chemical 51]

Racemic 7-chloro-5- (cyclopropylmethyloxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one (1.
7 g) was added to a Chiralcel-OD-H liquid chromatography column (10
% EtOH-supercritical carbon dioxide) to separate the enantiomeric constituents. The enantiomer that eluted earlier was the title compound (603 mg, mass spectrum (M + H) ⁺ C ₁₆ H ₁₉ F ₃ N ₂ O ₂ Cl calculated: 363.17076, found: 363.17088) as an amorphes solid. . This was assigned as the absolute configuration (S).

Example 31 7-Chloro-3-ethyl-5- (3-methyl-2-butenyloxy) -1,5
-Preparation of dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0215]

[Chemical 52]

The title compound (mp 158-160 ° C) was prepared according to the method of Example 29, substituting 3-methyl-2-butenol for cyclopropylmethanol.

Example 32 Preparation of 7-chloro-3-ethyl-5-allylthio-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0218]

[Chemical 53]

The title compound (mp 138.1-141.8 ° C.) was prepared according to the method of Example 29.
Prepared by substituting allyl mercaptan for cyclopropylmethanol.

Example 33 Preparation of 7-chloro-3-ethyl-5-cyclobutylmethyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0221]

[Chemical 54]

The title compound (calculated for mass spectrometry (M + H) ⁺ C ₁₇ H ₂₁ F ₃ N ₂ O ₂ Cl:
377.1244, found: 377.1262) was prepared according to Example 29 by substituting cyclobutylmethanol for cyclopropylmethanol.

Example 34 Preparation of 7-chloro-3-ethyl-5-cyclopropylmethylthio-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0224]

[Chemical 55]

The title compound (mp 152.3-156 ° C) was prepared according to the method of Example 29, substituting cyclopropylmethylmercaptan for cyclopropylmethanol.

Example 35 7-Chloro-3-ethyl-5- (1-methylcyclopropyl) methyloxy-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
Preparation of 2-one

[0227]

[Chemical 56]

The title compound (mp 171-172.5 ° C) was prepared according to the method of Example 29, substituting (1-methylcyclopropyl) methanol for cyclopropylmethanol.

Example 36 Preparation of 7-chloro-3-propyl-5-cyclopropylmethyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0230]

[Chemical 57]

The title compound (mp 155.5-157.5 ° C.) was prepared according to the method of Example 29.
Prepared by substituting n-propylamine for ethylamine.

Example 37 7-Fluoro-5- (cyclopropylmethoxy) -1,5-dihydro-5- (
Preparation of trifluoromethyl) -1,3-benzodiazepin-2-one

[0233]

[Chemical 58]

N-pivaloyl-4-fluoroaniline (10 g) in 150 mL dry THF
A 1.6 M hexane solution of butyllithium (77 mL) was added dropwise to the solution of 0. After stirring at 0 ° C. for 1 hour, ethyl trifluoroacetate (14.0 m
L) was added and the reaction mixture was allowed to warm to room temperature over 1.5 hours. The reaction was stopped by adding aqueous ammonium chloride solution and the mixture was partitioned between water and ether.
The ether layer was dried, concentrated to a brown oil (18.3 g) and used directly in the next reaction.

This oil was dissolved in 15 mL of ethylene glycol dimethyl ether, 75 mL of concentrated hydrochloric acid aqueous solution was added, and the mixture was refluxed for 1.5 hours. The cooled reaction mixture was diluted with water and made basic with solid sodium carbonate. It is extracted with ether, the extracts are dried and evaporated to an oil, which is purified by flash chromatography on silica gel (10-20% ethyl acetate-hexane) and recrystallised from ethyl acetate-hexane. After that, 2-amino-5-fluoro-1 ', 1', 1'-trifluoroacetophenone 216, 2.65 g was obtained.

A solution of about 15 mmol of diazomethane in 40 mL of ether was prepared by the manufacturer (Ald
D according to the instructions provided by the Rich Chemical Company.
Generated from 5 g of iazald®. This solution was treated with 2-amino-5-fluoro-1 ', 1', 1'-trifluoroacetophenone 2 in 10 mL of ether.
To 16 mL of a solution of 16 (2.65 g, 12.8 mmol) was added and the reaction mixture was stirred at room temperature for 5 hours. At this point it was shown to be completely converted to epoxide 217 by tlc. Excess diazomethane was destroyed by addition of acetic acid. To one half of this solution (containing about 6.5 mmol of epoxide) was added 10 mL of ethanol and the solution was concentrated on a rotary evaporator to an amount of about 10 mL. To this solution was added 1.69 mL of allylamine and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give a crude product, which was purified by flash chromatography on silica gel (10-50% ethyl acetate-hexane) to give product 218 as an oil 1.05 g.

To a solution of 218 (1.05 g, 3.77 mmol) in 20 mL dry THF,
N, N'-carbonyldiimidazole (856 mg) and triethylamine (
2.6 mL) was added and the reaction mixture was stirred overnight at ambient temperature. ethanol(
7 mL) was added and the mixture was refluxed for 6 hours. The cooled mixture was poured into water and this mixture was extracted twice with ethyl acetate. The combined extracts were dried over sodium sulphate and evaporated. Flash chromatography (20-50% EtOAc /
Hexane) gave 219 as a white solid (858 mg, 75%).

219 (850 mg) and pyridine (0.339 m) in 12 mL dry THF.
Thionyl chloride (0.407 mL) was added dropwise to the solution of L) at 0 ° C. After the addition was complete, the cooling bath was removed and stirring continued at ambient temperature for 30 minutes. The reaction mixture was partitioned between water and ethyl acetate and the organic layer containing dissolved and undissolved product was evaporated to give 220 as a crystalline product (785 mg, 87%).

To a solution of cyclopropylmethanol (0.624 mL) in 5 mL dry DMSO was added 100% sodium hydride (55 mg). It was stirred at ambient temperature for 30 minutes until the evolution of hydrogen ceased, after which 2 parts in DMSO (3.5 mL).
20 (250 mg) was added in one portion. After stirring at ambient temperature for 2 hours, the reaction mixture was partitioned between ether and aqueous citric acid solution, the organic layer was washed with brine, dried (sodium sulfate) and evaporated to 221 as a solid (240 mg). Got

A solution of 221 (135 mg) and rhodium trichloride hydrate (8 mg) in ethanol (10 mL) was refluxed for 1.5 hours. The mixture was cooled to 60 ° C., 1N hydrochloric acid (2.5 mL) was added and the mixture was stirred at 60 ° C. for 1 hour. The cooled mixture was partitioned between water and ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate solution and brine, dried and evaporated to an oil. Crystallization from ethyl acetate-hexane gave the title compound (55 mg, mp 198-199 ° C) as a colorless solid.

Example 38 Preparation of 7-Fluoro-3-ethyl-5-cyclopropylmethyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0242]

[Chemical 59]

The title compound (mp 156 ° C.) was prepared according to the method of Example 37, substituting ethylamine for allylamine, omitting the final deprotection step.

Example 39 Preparation of 7-Fluoro-5- (cyclobutylmethoxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0245]

[Chemical 60]

To a solution of cyclobutylmethanol (0.821 mL) in 5 mL dry DMSO was added 100% sodium hydride (63 mg). This was stirred at ambient temperature for 30 minutes until hydrogen evolution ceased, then 220 (2 mL) in DMSO (2 mL).
80 mg) was added once. After stirring at ambient temperature for 2 hours, the reaction mixture was partitioned between ether and aqueous citric acid solution, the organic layer was washed with brine, dried (sodium sulphate) and evaporated to give a crude product which was purified on silica gel. Purification by flash chromatography gave a solid (190 mg).

This solid in ethanol (13 mL) and rhodium trichloride hydrate (10 m
g) was refluxed for 1.5 hours. The mixture was cooled to 60 ° C. and 1N hydrochloric acid (3.5
mL) was added and the mixture was stirred at 60 ° C. for 1 hour. The cooled mixture was partitioned between water and ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate solution and brine, dried and evaporated to an oil. Crystallization from methylene chloride-hexane gave the title compound (55 mg, mp 190-191 ° C) as colorless crystals.

Example 40 Preparation of 7-Fluoro-3-ethyl-5-cyclobutylmethyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0249]

[Chemical formula 61]

The title compound (mp 137-138 ° C) was prepared according to the method of Example 39, substituting ethylamine for allylamine and omitting the final deprotection step.

Example 41 7-Chloro-5- [2- (1-methylcyclopropyl) ethynyl] -1,5-
Preparation of dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0252]

[Chemical formula 62]

A solution of about 60 mmol of diazomethane in 200 mL of ether was prepared by the manufacturer (Al
D Follow the instructions provided by Drich Chemical Company)
Produced from 10 g of iazald®. 30 mL of this solution
201 (11.15 g, 50 mmol) in and the reaction mixture was stirred at room temperature for 5 h. At this point it was shown to be completely converted to epoxide 202 by tlc. Excess diazomethane was quenched by the addition of acetic acid, 2,4-dimethoxybenzylamine (12 g) and 50 mL of ethanol was added,
The solution was concentrated on a rotary evaporator to a volume of about 60 mL. The mixture was stirred overnight at ambient temperature and then at 50 ° C. for 4 hours. After evaporating the solvent under reduced pressure, the crude product was dissolved in ether and the solution was washed twice with water. The ether layer was extracted twice with 1N HCl, the combined extracts were made basic with 1N NaOH and then extracted with ether. The ether extract was dried, evaporated and the crude product redissolved in methylene chloride, the solution washed with 1% aqueous acetic acid, brine, dried and evaporated 222 (13.2 g, 65%). %) Was obtained.

To a solution of 222 (13.0 g) in 150 mL dry THF was added N, N′-carbonyldiimidazole (6.5 g) and triethylamine (13 mL) and the reaction mixture was stirred at ambient temperature for 4 hours. . Ethanol (75 mL) was added and the mixture was refluxed overnight then evaporated to small volume. It was diluted with water and extracted twice with ethyl acetate. The combined extracts were dried, evaporated to a solid and triturated with methylene chloride to give 233 as colorless crystals (10.1 g, 73%).

A solution of 223 (2.92 g, 6.75 mmol) and pyridine (0.685 mL, 1.2 eq) in 30 mL of dry THF was added to thionyl chloride (0.54
0 mL, 1.1 eq) was added dropwise. After the addition was complete, the cooling bath was removed and stirring was continued for 1 hour at ambient temperature. The reaction mixture was partitioned between water and ethyl acetate and the organic layer containing dissolved and undissolved product was evaporated to give 224 as a crystalline product (2.4g, 79%).

(1-Methylcyclopropyl) acetylene (144) in dry THF (4 mL)
mg, 1.8 mmol) was added to a solution of 1.6 M butyllithium in hexane (0.99 mL, 1.58 mmol) at 0 ° C. After 30 minutes at 0 ° C., the mixture was cooled to −30 ° C. and 224 (200 mg, 0.45 mm) in THF (2 mL).
ol) was added dropwise. The reaction mixture was warmed to 0 ° C. over 30 minutes after which it was poured into aqueous citric acid solution and extracted twice with ether. The combined extracts were washed with brine, dried and evaporated to give 225 as 260 mg solid which was used directly in the next reaction.

A solution of 225 (250 mg) in trifluoroacetic acid (1.5 mL) was stirred at room temperature for 30 minutes, then poured into aqueous sodium bicarbonate solution and extracted with ethyl acetate.
The combined extracts were washed with brine, dried and evaporated to an impure solid.
This was purified by flash chromatography on silica gel (20-80% ethyl acetate-hexane) and then recrystallized from ether-ethyl acetate-hexane to give the title compound (6 mg, mp 196-198 ° C) as colorless crystals. It was

Example 42 Preparation of 7-chloro-5-cyclobutylmethyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0259]

[Chemical formula 63]

To a solution of cyclobutylmethanol (0.456 mL) in 7 mL dry THF,
Sodium hydride (110 mg) was added. After 30 minutes, THF (3.5 mL)
Chloride 224 (300 mg) in was added and the reaction mixture was stirred at ambient temperature for 1 h. The reaction was poured into saturated ammonium chloride and extracted with ethyl acetate. The extract was dried over magnesium sulphate and evaporated to give the crude product which was purified by flash chromatography (20-40% EtOAc / Hexanes) to give 124 mg of solid product.

A solution of this material in 2.5 mL trifluoroacetic acid was stirred at room temperature for 30 minutes then partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was dried and evaporated to a crude product which was flash chromatographed on silica gel (50%
Purified with ethyl acetate-hexane) to give the title compound (74 mg, mp 201.6-
202.9 ° C.) was obtained as colorless crystals.

Example 43 7-Chloro-5- (3-methyl-2-butenyloxy) -1,5-dihydro-
Preparation of 5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0263]

[Chemical 64]

The title compound ( ¹⁹ FNMR: δ-75.638 ppm) was prepared according to the method of Example 42 substituting 3-methyl-2-buten-1-ol for cyclobutylmethanol.

Example 44 Preparation of 7-chloro-5- (phenylmethyloxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0266]

[Chemical 65]

The title compound (mp 177-178 ° C) was prepared according to the method of Example 42 substituting benzyl alcohol for cyclobutylmethanol.

Example 45 7-Chloro-5-[(2-pyridyl) methyloxy] -1,5-dihydro-5
Preparation of-(trifluoromethyl) -1,3-benzodiazepin-2-one

[0269]

[Chemical formula 66]

The title compound (mp 233-235 ° C) was prepared according to the method of Example 42 substituting pyridine-2-methanol for cyclobutylmethanol.

Example 46 7-Chloro-5-[(1-methylcyclopropyl) methyloxy] -1,5-
Preparation of dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0272]

[Chemical formula 67]

The title compound (mp 211-212 ° C) was prepared according to the method of Example 42, substituting (1-methylcyclopropyl) methanol for cyclobutylmethanol.

Example 47 7-Chloro-5- (3-methylphenyloxy) -1,5-dihydro-5- (
Preparation of trifluoromethyl) -1,3-benzodiazepin-2-one

[0275]

[Chemical 68]

To a solution of m-cresol (0.259 mL) in 5 mL dry THF was added sodium hydride (41 mg) at room temperature. After 10 minutes, chloride 224 (300 mg) in THF (3.5 mL) was added and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction was poured into saturated ammonium chloride and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to give a white solid.

A solution of this material in 3 mL of trifluoroacetic acid was stirred at room temperature for 2 hours then partitioned between ethyl acetate and sodium bicarbonate. The organic layer was dried and evaporated to a crude product which was purified by flash chromatography on silica gel (35-50% ethyl acetate-hexane). Crystallization from chloroform and recrystallization from 10% ethyl acetate-hexane gave the title compound (25 mg, mp 137.1-140 ° C) as colorless crystals.

Example 48 7-Chloro-5- (cyclopropylmethylthio) -1,5-dihydro-5- (
Preparation of trifluoromethyl) -1,3-benzodiazepin-2-one

[0279]

[Chemical 69]

Cyclopropylmethyl mercaptan (532 mg) in 2.3 mL of dry THF
Sodium hydride (41 mg) was added to the above solution at room temperature. After 10 minutes, chloride 224 (200 mg) was added and the reaction mixture was stirred at ambient temperature for 1.5 hours. The reaction was poured into saturated ammonium chloride and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to give a white solid.

A solution of this material in 3 mL of trifluoroacetic acid was stirred at room temperature for 2 hours, then partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was dried and evaporated to give a solid which was twice from methylene chloride-hexane to give the title compound as a colorless solid (mp 175-177 ° C).

Example 49 Preparation of 7-chloro-5- (propylthio) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0283]

[Chemical 70]

The title compound (mp 156-157 ° C) was prepared according to the method of Example 48 substituting propanethiol for cyclopropylmethyl mercaptan.

Example 50 Preparation of 7-chloro-5- (2-propenylthio) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one

[0286]

[Chemical 71]

The title compound (mp 147.3-149 ° C) was prepared according to the method of Example 48 substituting allyl mercaptan for cyclopropylmethyl mercaptan.

[0288]

[Chemical 72]

[0289]

[Table 1]

[0290]

[Table 2]

[0291]

[Table 3]

[0292]

[Chemical formula 73]

[0293]

[Chemical 74]

[0294]

[Chemical 75]

[0295]

[Chemical 76]

[0296]

[Table 4]

[0297]

[Table 5]

[0298]

[Table 6]

[0299]

[Table 7]

[0300]

[Table 8]

[0301]

[Table 9]

[0302]

[Table 10]

[0303]

[Table 11]

[0304]

[Table 12]

[0305]

[Table 13]

[0306]

[Table 14]

[0307]

[Table 15]

[0308]

[Table 16]

[0309]

[Table 17]

[0310]

[Table 18]

[0311]

[Table 19]

[0312]

[Table 20]

[0313]

[Table 21]

[0314]

[Table 22]

[0315]

[Table 23]

[0316]

[Table 24]

[0317]

[Table 25]

[0318]

[Table 26]

[0319]

[Table 27]

[0320]

[Table 28]

[0321]

[Table 29]

[0322]

[Table 30]

[0323]

[Table 31]

[0324]

[Table 32]

[0325]

[Table 33]

[0326]

[Table 34]

[0327]

[Table 35]

[0328]

[Table 36]

[0329]

[Table 37]

[0330]

[Table 38]

[0331]

[Table 39]

[0332]

[Table 40]

[0333]

[Table 41]

[0334]

[Table 42]

[0335]

[Table 43]

[0336]

[Table 44]

[0337]

[Table 45]

[0338]

[Table 46]

(Use) The compound of the present invention has a reverse transcriptase inhibitory activity, particularly an HIV inhibitory effect. formula(
The compounds of I) have HIV reverse transcriptase inhibitory activity and are therefore useful as antiviral agents for HIV infection and related diseases. The compound of formula (I) has HIV reverse transcriptase inhibitory activity and is effective as an inhibitor of HIV growth. The ability of the compounds of the invention to inhibit viral growth or infectivity is demonstrated using standard assay methods for viral growth or infectivity, such as the assays described below.

The compounds of formula (I) of the present invention are also useful for the inhibition of HIV in ex vivo samples containing or predicted to be exposed to HIV. Thus, the compounds of the present invention may be used to inhibit HIV present in a bodily fluid sample (eg, serum or semen sample) that contains, or is suspected of containing, HIV or that is exposed to HIV. .

The compounds provided by the present invention may also be used as standard or reference compounds in tests or assays that measure the ability of agents to inhibit viral clonal replication and / or HIV reverse transcriptase, eg, in pharmaceutical research programs. Useful to do. Thus, the compounds of the present invention can be used as control or reference compounds in such assays and as quality control standards. The compounds of the invention can be provided in commercial kits or containers for use as such standard or reference compounds.

Since the compounds of the invention show specificity for HIV reverse transcriptase, the compounds of the invention may also be useful as diagnostic reagents in diagnostic assays detecting HIV reverse transcriptase. Thus, inhibition of reverse transcriptase activity in an assay by a compound of the invention (such as the assay described herein) would be indicative of the presence of HIV reverse transcriptase and HIV virus.

As used herein, “μg” refers to micrograms, “mg” refers to milligrams, “g” refers to grams, “μL” refers to microliters, and “m”.
"L" indicates milliliters, "L" indicates liters, "nM" indicates nonamolar concentrations, "μM" indicates micromolar concentrations, "mM" indicates millimolar concentrations,
"M" indicates molarity and "nm" indicates nonameter. "Sigma" is a product of Sigma-Aldrich Corp. of St. Louis, Missouri. Represents

HIV RNA Assay DNA plasmids and RNA transcripts in vitro: g of BH10 (bp 113-1816) cloned into PTZ 19R.
Plasmid pDAB72 containing both ag and pol sequences was constructed using Erickson
-Viitanen et al. AIDS Research and Hu
Prepared according to man Retroviruses 1989, 5, 577.
After linearization of this plasmid with Bam HI, an in vitro RNA transcript was generated using the Riboprobe Gemini System II kit (Promega) with T7 RNA polymerase. The synthesized RNA was treated with RNase (RNAse) -free DNase (DNAse) (Promega), extracted with phenol-chloroform, and precipitated with ethanol for purification. RNA transcripts were dissolved in water and stored at -70 ° C. The concentration of RNA was measured by A _{26 0.}

Probes: Biotinylated capture probes are available from Applied Biosystems (Fos
ter City, CA) DNA synthesizer, Cocuzza
, Tet. Lett. Biotin-phosphoramidite reagent of 1989, 30, 6287 was used to synthesize by adding biotin to the 5'end of the oligonucleotide, and then purified by HPLC. gag biotinylated capture probe (5-biotin-CT
AGCTCCCTGCTTGCCCATACTA 3 ') was complementary to nucleotides 889-912 of HXB2, and the pol biotinylated capture probe (5'-biotin-CCCTATCATTTTTGGTTTCCAT 3') was complementary to nucleotides 2374-2395 of HXB2. Alkaline phosphatase-conjugated oligonucleotides used as reporter probes are Syngene (
Manufactured by San Diego, California). The pol reporter probe (5 'CTGTCTTACTTTGAATAAAACCTC 3') was HXB.
2 was complementary to nucleotides 2403-2425. The gag reporter probe (5 ′ CCCAGTATTTTGTCTACAGCCTTCT 3 ′) is
It was complementary to nucleotides 950-973 of HXB2. All nucleotide positions are Genetics Computer Group Sequence
Analysis Software Package (Devereau N)
U.S.A. GenBank Genetic Sequence Data, accessed by Uccleic Acids Research 1984, 12, 387).
Bank's. This reporter probe is 2xSSC (0.3 MNa
Cl, 0.03M sodium citrate), 0.05M Tris pH 8.8, 1
Prepared as a 0.5 μM stock solution in mg / mL BSA. The biotinylated capture probe was prepared as a 100 μM stock solution in water.

Streptavidin-Coated Plates: Streptavidin-coated plates are available from DuPont Biotechnology Systems (
Boston, Mass.).

Cell and viral stocks: MT-2 and MT-4 cells are 5% fetal calf serum (FC) in the case of MT-2 cells.
S) or in the case of MT-4 cells RPMI164 supplemented with 10% FCS, 2 mM L-glutamine and 50 μg / mL gentamicin (all from Gibco).
Maintained at 0. HIV-1 RF was grown in MT-4 cells in the same medium.
Virus stocks were prepared about 10 days after acute infection of MT-4 cells and stored in aliquots at -70 ° C. The infectious titer of HIV-1 (RF) stock is MT-
It was 1-3 × 10 ⁷ PFU (plaque forming units) / mL as determined by plaque assay on two cells (see below). Each aliquot of virus stock used for infection was thawed only once.

To assess antiviral efficacy, infected cells were subcultured for 1 day before infection. On the day of infection, cells were 5x10 ⁵ cells / mL in RPMI 1640, 5% FCS for bulk infection and 5% F for infection in microtiter plates.
The cells were resuspended in Dulbecco's modified Eagle medium containing CS at 2 × 10 ⁶ / mL. Virus was added and cultivation was continued at 37 ° C. for 3 days.

HIV RNA Assay: Cell lysates or purified RNA in 3M or 5M GED were mixed with 5M GED and capture probe to give a final concentration of guanidinium isothiocyanate of 3M and a final concentration of biotin oligonucleotide. Was set to 30 nM. Hybridizations were performed in sealed U-bottom 96 well tissue culture plates (Nunc or Costar) at 37 ° C. for 16-20 hours. RNA hybridization reactions were diluted 3-fold with deionized water to a final concentration of guanidinium isothiocyanate of 1M and aliquots (150 μL) were transferred to wells of streptavidin-coated microtiter plates. Binding of capture probes and capture probe-RNA hybrids to immobilized streptavidin was allowed to proceed for 2 hours at room temperature, after which the plates were DuPont ELISA plate wash buffer (phosphate buffered saline (PBS), 0. It was washed 6 times with 05% Tween 20). A second hybridization of the reporter probe to the immobilized complex of the target RNA hybridized with the capture probe was performed with 4xSSC, 0.66% Triton X100, 6.66% depletion in washed streptavidin coated wells. This was done by adding 120 μl of hybridization cocktail containing ionized formamide, 1 mg / mL BSA and 5 nM reporter probe. After hybridizing at 37 ° C. for 1 hour, the plate was washed again 6 times. The immobilized alkaline phosphatase activity was measured using 0.2 mM buffer δ (2.5 M diethanolamine, pH 8.9 (JBL Scientific), 10 mM MgCl ₂ , 5 mM zinc acetate dihydrate and N-hydroxyethyl-ethylene-diamine-triamine. 4-Methylumbelliferyl phosphate in acetic acid) (MUBP, JBL
(Scientific) was detected by adding 100 μL. The plate was incubated at 37 ° C. Fluorescence at 450 nM was measured using a microplate fluorometer (Dynatek) that excites at 365 nM.

Evaluation of microplate-based compounds in MT-1 cells infected with HIV-1: Compounds to be evaluated were dissolved in DMSO up to twice the highest concentration tested.
And diluted to medium up to 2% of maximum DMSO concentration. 3 of the compound in the medium
Double serial dilutions were performed directly in U-bottom microtiter plates (Nunc). After compound dilution, MT-2 cells (50 μL) were added to give a final concentration of 5 × 1 per mL.
The number was set to 0 ⁵ (1 × 10 ⁵ per well). The cells were incubated with the compounds for 30 minutes at 37 ° C. in a CO ₂ incubator. To assess antiviral potency, appropriate dilutions of HIV-1 (RF) virus stock (50 μL) were added to culture wells containing dilutions of cells and test compounds. The final volume in each well is 20
It was 0 μL. Eight wells per plate were left uninfected by adding 50 μL of medium instead of virus, while eight wells were infected without antiviral compound. To assess compound toxicity, equal plates were cultured without virus infection.

After incubation for 3 days at 37 ° C. in a humidified chamber in a CO ₂ incubator, all but 25 μL medium / well were removed from HIV-infected plates. 37 μL of 5 M GED containing biotinylated capture probe was added to the sedimented cells and residual medium in each well for a final concentration of 3 MGED and 30 nM capture probe. Hybridization of the capture probe to HIV RNA in cell lysates was performed in a plate sealer (Costa) in microplate wells similar to those used for virus culture.
The plate was sealed in r) and incubated in a 37 ° C. incubator for 16-20 hours. Distilled water was then added to each well to dilute the hybridization reaction 3-fold and 150 μL of this diluted mixture was transferred to streptavidin-coated microtiter plates. HIV RNA was quantified as described above. To measure the amount of viral RNA produced during infection, a known amount of pDA was used.
A standard curve generated by adding B72 in vitro RNA transcripts to wells containing lysed uninfected cells was performed on each microtiter plate.

To standardize the viral inoculum used to evaluate compounds for antiviral activity, virus dilutions were performed at IC ₉₀ values (compound concentration required to reduce HIV RNA levels by 90%) dideoxycytidine. 0.2μ in (ddC)
It was selected to be g / mL. The IC ₉₀ values of other antiviral compounds, both stronger and less potent than ddC, were reproducible using several stocks of HIV-1 (RF) when this method was followed. there were. This virus concentration corresponds to about 3 × 10 ⁵ PFU per assay well (measured by plaque assay in MT-2 cells) and typically yields about 75% of the highest viral RNA levels achievable with any virus inoculum. Generated. In the HIV RNA assay, the IC ₉₀ value is the net signal in the RNA assay (the signal from the infected cell sample minus the signal from the uninfected cell sample) relative to the net signal of infected, untreated cells in the same culture plate. Calculated from percent reduction. The effectiveness of each infection and RNA assay test was judged by three criteria. Viral infection was required to generate an RNA assay signal equal to or greater than the signal generated from 2 ng of pDAB 72 in vitro RNA transcript. IC ₉₀ for ddC calculated by each test operation is 0
． Must be between 1 and 0.3 μg / mL. Finally, the plateau level of viral RNA produced by an effective reverse transcriptase inhibitor should be less than 10% of the level achieved with an uninhibited infection.

For antiviral potency testing, all manipulations in microtiter plates after the initial addition of a double concentrated compound solution to a row of wells were performed on a Perkin El
Performed using mer / Cetus ProPette.

Compounds tested in the above assay are considered active if they exhibit an IC ₉₀ ≦ 20 μM. Preferred compounds of the invention have an IC ₉₀ of ≦ 5 μM. More preferred compounds of the invention have an IC ₉₀ of ≦ 0.5 μM. Even more preferred compounds of the invention have IC ₉₀ 's of ≦ 0.05 μM. Even more preferred compounds of the invention have an IC ₉₀ of ≦ 0.005 μM.

Using the methods described above, it was discovered that some compounds of the invention exhibited an IC ₉₀ of ≦ 20 μM, thereby confirming their use as effective HIV inhibitors. ..

Protein Binding and Mutation Resistance To characterize the clinical efficacy of NNRTI analogs, the effect of plasma proteins on antiviral potency and amino acid changes at known binding sites for HIV wild type and NNRTI. Measures of antiviral potency against the occurring variants of HIV were examined. There are two principles of this test method.

1. Many drugs bind extensively to plasma proteins. Although the binding affinity of most drugs to the main components of human plasma, namely human serum albumin (HSA) or alpha-1-acid glycoprotein (AAG), is low, these major components are present in blood at high concentrations. . Only free or unbound drug is available to cross the infected cell membrane and interact with the target site (ie HIV-1 reverse transcriptase, HIV-1RT). Therefore, added HSA + AAG in tissue culture
The antiviral potency of is more closely reflected in the potency of a given compound in the clinical setting. The concentration of the compound required to inhibit viral replication by 90%, determined by a sensitive viral RNA-based detection method, is designated IC90. The fold increase in apparent IC90 of the test compound was then calculated at the current or additional levels of HSA and AAG, which reflected in vivo concentrations (HSA 45 mg / ml, AAG 1 mg / ml). The lower the rate of increase, the more useful the compound will be in interacting with the target site.

2. The high rate of viral replication in infected individuals combined with the poor compatibility of viral RT results in the production of quasispecies or mixtures of HIV species in infected individuals. These species include the major wild species, but also HIV variants, and the percentage of a given variant reflects its relative fitness and replication rate. Since the mutants, including mutants with changes in the amino acid sequence of viral RT, are likely to already exist in the quasispecies of infected individuals, the ultimate capacity observed in the clinical case is not only wild type HIV-1 but also mutant Will also reflect the drug's ability to inhibit. Therefore, from the known basic knowledge of genes, we constructed mutant forms of HIV-1 having amino acid substitutions at positions thought to be involved in NNRTI binding, and determined the ability of test compounds to inhibit the replication of these mutant viruses. It was measured. Susceptible virus R
The concentration of compound required for 90% inhibition of viral replication measured by the NA-based detection method is designated IC90. It is desirable to obtain compounds with high activity against various mutants.

Dose and Formulation The antiviral compounds of the present invention are useful for treating the active agent and site of action of the agent in the mammalian body,
Thus, it can be administered for the treatment of viral infections by any means that results in contact with viral reverse transcriptase. They can be administered as individual therapeutic agents or in combination with therapeutic agents by any conventional means useful for use in connection with pharmaceuticals. These compounds can be administered alone, but are preferably administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

Of course, the dosage will depend on known factors, such as the pharmacodynamic properties of the individual agents and their mode and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, type of concurrent treatment. , The frequency of treatment, and the effect desired.
A daily dose of the active ingredient can be from about 0.001 to about 1000 milligrams per kilogram body weight, with a preferred dose being about 0.1 to about 30 mg / kg.

Dosage forms of the composition suitable for administration comprise from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. The active ingredient can be administered orally in solid dosage forms such as capsules, pills and powders, or in liquid dosage forms such as elixirs, syrups and suspensions. It can also be administered parenterally in a sterile liquid dosage form.

Gelatin capsules include the active ingredient and powder carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like.
Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to block any unpleasant flavors and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, suitable oils, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. For suitable pharmaceutical carriers, see Remington's Pharmaceutical Sciences, a standard reference text in the field.
, Above. ”

Useful pharmaceutical dosage forms of the compounds of the invention can be illustrated as follows.

Capsules A number of unit capsules may be prepared by filling standard two-piece hard gelatin capsules each with 100 mg powdered active ingredient, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate.

Soft Gelatin Capsule A soft gelatin capsule containing 100 mg of active ingredient prepared by preparing a mixture of the active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil and injecting it into gelatin using a positive displacement pump. Can be formed. The capsules should then be washed and dried.

(Tablets) The dosage unit is 100 mg of the active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 m of starch.
Numerous tablets can be prepared by conventional procedures to give g and lactose 98.8 mg.
Appropriate coatings can be applied to increase palatability or delay absorption.

(Suspension) 5 mL of each was finely pulverized active ingredient 25 mg, sodium carboxymethyl cellulose 200 mg, sodium benzoate 5 mg, sorbitol solution (USP) 1
． Aqueous suspensions for oral administration can be prepared to contain 0 g and 0.0025 mg vanillin.

(Injection) A parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of the active ingredient in 10% by volume propylene glycol and water.
The solution is sterilized by commonly used techniques.

(Combination of Components (a) and (b)) Each therapeutic agent component of the present invention can be independent in any dosage form as described above, and can be administered by various methods as described above. can do. In the description below, component (b) should be understood to represent one or more agents as previously described. Thus, if components (a) and (b) are treated similarly or independently, then each agent of component (b) can be treated similarly or independently.

Ingredients (a) and (b) of the present invention are formulated together in a single dosage unit (ie, combined together in a single capsule, tablet, powder or solution etc.) as a combination product. It is possible. When components (a) and (b) are not formulated together in a single dosage unit, component (a) can be administered simultaneously with component (b) or in any order. For example, it is possible to administer component (a) of the present invention first, and then component (b), or vice versa. If component (b) comprises more than one drug, for example one RT inhibitor and one protease inhibitor, these drugs can be administered together or in any order. When not administered simultaneously, administration of components (a) and (b) is preferably separated by less than about 1 hour. The route of administration of components (a) and (b) is preferably oral. As used herein, terms such as oral agents, oral inhibitors, oral compounds and the like refer to compounds that can be administered orally. It is preferred that both components (a) and (b) be administered by the same route (ie, eg, orally together) or in the same dosage form, but if desired, each may be administered by a different route (ie, eg, It is possible to administer one component of the combination product orally, the other component intravenously), or in different dosage forms.

As will be appreciated by those skilled in the art, the doses of the combination therapies of the invention will depend on the pharmacokinetic properties of the individual agents and their mode and mode of administration, as described above. It can vary depending on various factors such as age, health and weight, nature and extent of symptoms, type of combination treatment, frequency of treatment, and desired effect.

The specific doses of components (a) and (b) of the present invention will be readily ascertainable by one of ordinary skill in the art based on the present disclosure. According to general guidance, a daily dose will typically be 100 milligrams to about 1.5 grams of each ingredient. When component (b) is more than one, typically the daily dose of component (b) will be from about 100 milligrams to about 1.5 grams of each drug. According to the general guidance, when the compounds of component (a) and component (b) are administered in combination, the dose of each component is such that the usual dose of component is
Approximately 70-8 compared to when administered alone as a single agent for the treatment of IV infection
It is possible to reduce it to 0%.

The combination products of the present invention may be formulated such that the active ingredients are combined in a single dosage unit but physical contact between the active ingredients is minimized. To minimize contact, it is possible to enterically coat one active ingredient, for example when the product is administered orally. Not only is it possible to minimize the contact between the active ingredients brought together by enteric coating one of the active ingredients, but also to release one of these ingredients in the intestine rather than in the stomach. As such, it is possible to control the release of one of these components in the gastrointestinal tract. In another embodiment of the invention where oral administration is desired, one of the active ingredients is effective for sustained release throughout the gastrointestinal tract and serves to minimize physical contact between the active ingredients taken together. A combination product coated with a sustained release material is provided. Moreover, the sustained release component can be additionally enteric coated so that release of this component occurs only in the intestine. In yet another approach, one component is coated with a sustained release and / or enteric release polymer to further separate the active ingredients and the other component is also a low viscosity grade hydroxypropylmethylcellulose or known in the art. Formulations of combination products coated with polymers such as other suitable materials are included. This polymer coating functions to form an additional barrier to interaction with other components. In each formulation where contact between components (a) and (b) is prevented by a coating or some other substance, contact between the individual agents of component (b) can also be prevented.

The dosage form of the combination product of the present invention in which one active ingredient is enterically coated is such that the enterically coated ingredient and the other active ingredient are blended together and then compressed into tablets or enteric coated. The coated ingredients can be compressed in one layer of the tablet and the other active ingredient in the form of a tablet compressed in an additional layer. Optionally, one or more placebo layers can be present such that the placebo layer is between the layers of active ingredient to further separate the two layers. Further, the dosage form of the present invention is
One active ingredient in the form of a capsule compressed into one tablet or in the form of a plurality of microtablets, microparticles, granules or non-peril,
These can then be enteric coated. These enteric-coated microtablets, microparticles, granules or non-perils are then encapsulated or compressed with granules of other active ingredients into capsules.

Other methods of minimizing contact between these as well as the components of the combination products of the present invention, whether administered in a single dosage form, simultaneously or in a similar manner, but in separate forms. Whether administered, it will be readily apparent to one of skill in the art based on the present disclosure.

A medicament useful in the treatment of HIV infection, comprising a therapeutically effective amount of a pharmaceutical composition comprising a compound of component (a) and one or more component (b) in one or more sterile containers. Kits are also within the scope of the invention. Sterilization of the container can be carried out using conventional sterilization methods well known to those skilled in the art. Component (a) and component (b) can be in the same sterile container or different sterile containers. Sterile containers of these materials can optionally include different containers or one or more multi-part containers. Component (a) and component (b) can be separated or physically combined in a single dosage form or unit as described above. As will be readily appreciated by those skilled in the art, such kits may further include, for example, one or more pharmaceutically acceptable carriers, additional vials for mixing the components, etc., if desired. , One or more of various conventional pharmaceutical kit components can be included. Instructions that direct the amount of ingredients to be administered, guidelines for administration and / or guidelines for mixing the ingredients,
It can also be included in the kit as an insert or as a label.

Obviously, many modifications and variations of the present invention are possible in light of the above teachings. Therefore, it is to be understood that within the scope of the appended claims, the invention may be practiced other than as specifically described herein.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 31/18 A61P 31/18 4C086 37/04 37/04 43/00 111 43/00 111 C07D 267/06 C07D 267/06 281/02 281/02 401/06 401/06 401/12 401/12 405/06 405/06 409/06 409/06 471/04 471/04 487/04 487/04 (81) designation Country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), EA (AM, AZ, BY, KG , KZ, MD, RU, TJ, TM), AU, BR, CA, CZ, EE, HU, IL, IN, JP, KR, LT, LV, MX, NO, NZ, PL, RO, SG, SI , SK, UA, VN, ZA (72) Inventor Anso Over Jay. Kokuttsua United States 19809 Wilmington, Delaware Lighthouse Road 306 F-term (reference) 4C036 AB02 AB05 AB09 AB10 AB16 AB17 AB20 4C050 AA01 BB08 CC11 EE04 FF02 GG03 GG06 HH01 HH04 4C056 AA03 AB01 AC02 AD03 AE03 FA03 FB05 FB07 FC01 FC02 4C063 AA01 BB03 BB08 CC37 CC75 CC92 DD12 EE01 4C065 AA04 AA05 BB15 CC01 DD03 EE02 HH01 JJ01 JJ02 KK02 KK09 LL03 LL04 LL09 PP01 PP03 PP04 PP12 4C086 AA01 AA02 AA03 BC56 CB11 GA02 GA04 GA07 GA08 MA01 MA02 MA03 MA20 MA05 MA04 MA20 MA04 MA20 MA04 MA20 MA04 MA20 MA04 MA20 MA05

Claims (19)

[Claims] 1. A novel compound of formula I, embedded image Alternatively, its stereoisomer or its pharmaceutically acceptable salt form. Wherein A is O or S, B is selected from O, S, and NR ⁸ , W is N or CR ³ , X is N or CR ^3a , Y is N or CR ^3b And Z is N or CR ^3c , provided that when two of W, X, Y, and Z are N, the rest are other than N, and R ¹ is substituted with 0 to 7 halogens. is selected from C _{1 ~ 3} alkyl group and a cyclopropyl which is, R ^{2 is, -R 2c, -OR 2c, -OCHR} 2a R 2b, -OCH 2 CHR 2a R 2b, -O (
CH ₂ ) ₂ CHR ^2a R ^2b , -OCHR ^2a C = C-R ^2b , -OCHR ^2a C = R ^2c ,-
^{OCHR 2a C≡C-R 2b, -SR} 2c, -SCHR 2a R 2b, -SCH 2 CHR 2a R 2 b, -S (CH 2) 2 CHR 2a R 2b, -SCHR 2a C = C-R 2b, -SCHR2 ^a C
^{= R 2c, -SCHR 2a C≡C-} R 2b, -NR 2a R 2c, -NHCHR 2a R 2b, -N
_{^{HCH 2 CHR 2a R 2b, -NH}} (CH 2) 2 CHR 2a R 2b, -NHCHR 2a C = C
—R ^2b , —NHCHR ^2a C═R ^2c , and —NHCHR ^2a C≡C—R ^2b , wherein R ^2a is H, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , and CH. is selected from the group of ₂ CH ₂ CH _3, R ^2b is H or R ^2C, R ^2c is 0-2 C _{1 ~ 6} alkyl substituted with R ^4, substituted with 0-2 R ⁴ has been C _{2 - 5} alkenyl, 0-1 R ⁴ C _{2 - 5} alkynyl substituted with, 0-2 C ₃ substituted with R ^3d of _1-6 cycloalkyl, 0-2 R ^3d A phenyl substituted with
And 1 to 3 heteroatoms selected from the group of O, N, and S,
Selected from the group of 3 to 6 membered heterocyclic groups substituted with 2 R ^3d , or, alternatively, the —NR ^2a R ^2c group has 0 to 1 carbon atom substituted with O or NR ⁵ . represents a 4-7 membered cyclic amine, R ³ is H, C _{1 ~ 4} alkyl, -OH, C _{1 ~ 4 alkoxy, OCF 3, F, Cl,} B
^{r, I, -NR 5 R 5a} , -NO 2, -CN, -C (O) R 6, -NHC (O) R 7,
^{-NHC (O) NR 5 R 5a} , -NHSO 2 R 10, -SO 2 NR 5 R 5a, and O, N
, And is selected from the group of 5- to 6-membered heteroaromatic ring containing 1-4 heteroatoms selected from the group of S, R ^3a is H, C _{1 ~ 4} alkyl, -OH, C _{1 ~ 4} alkoxy, OCF ₃ , F, Cl,
^{Br, I, -NR 5 R 5a} , -NO 2, -CN, -C (O) R 6, -NHC (O) R 7, -NHC (O) NR 5 R 5a, -NHSO 2 R 10, - SO ₂ NR ⁵ R ^5a , and O,
Selected from the group of 5 to 6 membered heteroaromatic rings containing 1 to 4 heteroatoms selected from the group of N, and S, or alternatively, R ³ and R ^3a together represent —OCH ₂ O— formed, R ^3b is H, C _{1 ~ 4} alkyl, -OH, C _{1 ~ 4} alkoxy, OCF _3, F, Cl,
^{Br, I, -NR 5 R 5a} , -NO 2, -CN, -C (O) R 6, -NHC (O) R 7, -NHC (O) NR 5 R 5a, -NHSO 2 R 10 and, It is selected from the group of -SO ₂ NR ⁵ R ^5a, or, R ^3a and R ^3b are formed a -OCH ₂ O-together, R ^3c is, H, C _{1 ~ 4} alkyl, -OH, C _{1 ~ 4} Alkoxy, OCF ₃ , F, Cl
^{, Br, I, -NR 5 R} 5a, -NO 2, -CN, -C (O) R 6, -NHC (O)
R ⁷ , —NHC (O) NR ⁵ R ^5a , —NHSO ₂ R ¹⁰ , and —SO ₂ NR ⁵ R ^5a , or R ^3b and R ^3c together form —OCH ₂ O—. and, for each R ^3d is appearing, C _{1 ~ 4} alkyl, -OH, C _{1 ~ 4} alkoxy, OCF _3,
F, Cl, Br, I, -NR 5 R 5a, -NO 2, -CN, -C (O) R 6, -NH
^{C (O) R 7, -NHC} (O) NR 5 R 5a, -NHSO 2 R 10, and -SO ₂ NR ⁵ independently from the group consisting of R ^5a is selected, each R ^3e is appearing, C _{1 1-4} alkyl, -OH, C _{1 - 4} alkoxy, OCF _3,
F, Cl, Br, I, -NR 5 R 5a, -NO 2, -CN, -C (O) R 6, -NH
^{C (O) R 7, -NHC} (O) NR 5 R 5a, -NHSO 2 R 10, and -SO ₂ NR ⁵ independently from the group consisting of R ^5a is selected, each R ^3f is appearing, C _{1 1-4} alkyl, -OH, C _{1 - 4} alkoxy, OCF _3,
F, Cl, Br, I, -NR 5 R 5a, -NO 2, -CN, -C (O) R 6, -NH
^{C (O) R 7, -NHC} (O) NR 5 R 5a, -NHSO 2 R 10, and -SO ₂ NR ⁵ independently from the group consisting of R ^5a is selected for each the R ^3g appearing, C _{1 1-4} alkyl, -OH, C _{1 - 4} alkoxy, OCF _3,
F, Cl, Br, I, -NR 5 R 5a, -NO 2, -CN, -C (O) R 6, -NH
^{C (O) R 7, -NHC} (O) NR 5 R 5a, -NHSO 2 R 10, -SO 2 NR 5 R 5a
Comprises 0-3 C _{3 ~ 10} carbocyclic and O substituted with R ^3f, N, and 1-3 heteroatoms selected from the group of S, substituted with 0-3 R ^3f 5-10 done
Are independently selected from the group of membered heterocyclic group, R ⁴ is, F, Cl, Br, I , 0~2 amino C _{1 ~ 6} alkyl substituted with R ^3e, 0
To 2 pieces of C _{3 ~ 10} carbocyclic ring substituted with R ^3e, comprises 0-5 phenyl substituted with R ^3e, and O, and 1-3 heteroatoms selected from N and S, 0-2
Is selected from the group of heterocyclic groups substituted 5-10 membered by number of R ^3e, R ⁵ and R ^5a are independently selected from the group of H and C _{1 ~ 4} alkyl, or, R ⁵ and R ^5a together with the nitrogen attached to them are 0
To form a 5- or 6-membered ring containing ~ 1 one O or N atom, R ⁶ is, H, OH, is selected from the group of C _{1 ~ 4} alkyl, C _{1 ~ 4} alkoxy, and NR ⁵ R ^5a, R ⁷ is selected from the group of C _{1 ~ 3} alkyl and C _{1 ~ 3} alkoxy, R ^{8 is, H, oR 9, SR 9} , NR 5 R 9, substituted with 0-3 R ^{3 g} C _1-6 alkyl, 0-3 C _{2 ~ 6} alkenyl substituted with R ^{3 g,} 0-3 C _{2 ~ 6} alkynyl substituted with R ^{3 g,} substituted with 0-2 R ^3f C _{3 ~ 5} cycloalkyl, 0
Phenyl substituted with ~ 5 R ^3f , and 5-6 members substituted with 0-2 R ^3f containing 1-3 heteroatoms selected from the group O, N, and S. is selected from the group of the heterocyclic group, R ⁹ is 1-3 heteroatoms selected from the group of 0-5 C _{3 ~ 10} carbocyclic and O substituted with R ^3f, N, and S 5 containing an atom and substituted with 0-2 R ^3f
Is selected from the group of 10-membered heterocyclic group, R ¹⁰ is selected from C _{1 ~ 4} alkyl and phenyl. ] 2. A compound according to claim 1, B is NR ^8, R ¹ is selected from the group of one to seven C ₁ substituted with a halogen _1-3 alkyl and cyclopropyl , R ² is —R ^2c , —OR ^2c , —OCHR ^2a R ^2b , —OCH ₂ CHR ^2a R ^2b , —O (
CH ₂ ) ₂ CHR ^2a R ^2b , -OCHR ^2a C = C-R ^2b , -OCHR ^2a C = R ^2c ,-
^{OCHR 2a C≡C-R 2b, -SR} 2c, -SCHR 2a R 2b, -SCH 2 CHR 2a R 2 b, -S (CH 2) 2 CHR 2a R 2b, -SCHR 2a C = C-R 2b, -SCHR ^2a C
═R ^2c , and —SCHR ^2a C≡C—R ^2b , wherein R ^2a is H, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , and CH ₂ CH ₂ CH ₃ is selected, R ^2b is H or R ^2c, R ^2c is 0-2 C _{1 ~ 5} alkyl substituted with R ^4, C _{2 ~ 5} substituted with 0-2 R ⁴ alkenyl, 0-1 C _{2 ~ 5} alkynyl substituted with R ^4, 0-2 C substituted with R ^3d _{3 ~ 6} cycloalkyl, and substituted with 0-2 R ^3d phenyl is selected from the group of, for each R ³ is appearing, H, C _{1 ~ 4} alkyl, OH, C _{1 ~ 4} alkoxy, F, Cl
^{, Br, I, NR 5 R} 5a, NO 2, -CN, C (O) R 6, NHC (O) R 7, NH
C (O) NR ⁵ R ^5a and independently selected from the group of 5 to 6 membered heteroaromatic rings containing 1 to 4 heteroatoms selected from the group of O, N and S, R ^3a in each occurrence, H, C _{1 ~ 4} alkyl, -OH, C _{1 ~ 4} alkoxy, F, C
1, Br, I, NR ⁵ R ^5a , NO ₂ , —CN, C (O) R ⁶ , NHC (O) R ⁷ , N
HC (O) NR ⁵ R ^5a and independently selected from the group of 5 to 6 membered heteroaromatic rings containing 1 to 4 heteroatoms selected from the group of O, N and S, or , R ³ and R ^3a form a -OCH ₂ O-together, each is R ^3b appearing, H, C _{1 ~ 4} alkyl, OH, C _{1 ~ 4} alkoxy, F, Cl
, Br, I, NR ⁵ R ^5a , NO ₂ , —CN, C (O) R ⁶ , NHC (O) R ⁷ , and NHC (O) NR ⁵ R ^5a independently selected, or, R ^3a and R ^3b form a -OCH ₂ O-together, R ⁴ is, Cl, F, 0~2 amino C _{1 ~ 4} alkyl substituted with R ^3e, 0 to 2 amino R ^{3 e} in substituted C _{3 ~ 5} carbon ring, phenyl substituted with 0-5 R ^3e, and O
, N, and S selected from the group of 5 to 6 membered heterocyclic groups containing 1 to 3 heteroatoms selected from the group substituted with 0 to 2 R ^3e , R ⁵ and R ^5a is independently selected from the group of H, CH ₃ and C ₂ H ₅ , R ⁶ is of H, OH, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ , and NR ⁵ R ^5a . Selected from the group, R ⁷ is CH ₃ , C ₂ H ₅ , CH (CH ₃ ) ₂ , OCH ₃ , OC ₂ H ₅ , and OCH (C
A compound selected from the group H ₃ ) ₂ and R ⁸ selected from the group H, cyclopropyl, CH ₃ , C ₂ H ₅ , and CH (CH ₃ ) ₂ . 3. The compound according to claim 2, wherein R ¹ is selected from the group of CF ₃ , C ₂ F ₅ and cyclopropyl, and R ² is —R ^2c , —OR ^2c , —OCHR. ^2a R ^2b , -OCH ₂ CHR ^2a R ^2b , -OC
HR ^2a C = C-R ^2b , -OCHR ^2a C = R ^2c , -OCHR ^2a C≡C-R ^2b , -S
^{R 2c, -SCHR 2a R 2b,} -SCH 2 CHR 2a R 2b, -SCHR 2a C = C-R 2b
, -SCHR ^2a C = R ^2c , and -SCHR ^2a C≡C-R ^2b ,
R ^2a is selected from H, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , and CH ₂ CH ₂ CH ₃ , R ^2b is H or R ^2c , and R ^2c is 0 to 2 R C _{1 ~ 3} alkyl substituted with ^4, 0-2 C _{2 ~ 3} alkenyl substituted with R ^4, 0 to 1 amino C _{2 ~ 3} alkynyl substituted with R ^4, and 0
A two C _{3 ~ 6} cycloalkyl substituted with R ^3d, each R ³ is Degen, H, C _{1 ~ 3} alkyl, OH, C _{1 ~ 3} alkoxy, F, Cl
^{, Br, I, NR 5 R} 5a, NO 2, -CN, C (O) R 6, NHC (O) R 7, NH
Independently selected from the group of C (O) NR ⁵ R ^5a , or R ³ and R ^3a together form —OCH ₂ O—, R ^3b is H, R ^3c is H, each R ^3e is appearing, H, C _{1 ~ 4} alkyl, -OH, C _{1 ~ 4 alkoxy, OCF 3, F, Cl,} -NR 5 R 5a, -C (O) R 6, -SO 2 NR ⁵ is independently selected from the group of R ^5a, R ⁴ is, Cl, F, 0~1 amino C _{1 ~ 4} alkyl substituted with R ^3e, C substituted with 0-2 R ^{3 e} _3-5 carbocycle and 0-2 phenyl substituted with R ^3e, O
, N, and S selected from the group of 5-6 membered heterocyclic groups containing 1-3 heteroatoms selected from the group substituted with 0 to 1 R ^3e , R ⁵ and R ^5a is independently selected from the group of H, CH ₃ and C ₂ H ₅ , and R ⁶ is a group of H, OH, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ , and NR ⁵ R ^5a . R ⁷ is selected from the group of CH ₃ , C ₂ H ₅ , OCH ₃ and OC ₂ H ₅ , and R ⁸ is selected from the group of H, cyclopropyl, CH ₃ and C ₂ H ₅ . The compound of choice. 4. The compound according to claim 3, wherein R ¹ is CF ₃ , R ² is —R ^2c , —OR ^2c , —OCH ₂ R ^2b , —OCH ₂ CH ₂ R. ^2b, -OCH ₂ C =
_{^{C-R 2b, -OCH 2 C≡C}} -R 2b, -SR 2c, -SCH 2 R 2b, -SCH 2 CH 2 R 2b, -SCH 2 C = C-R 2b, and -SCH ₂ C [identical to] C is selected from the group of -R ^2b, ethyl R ^2b is H or R ^2c, R ^2c is substituted methyl substituted with 0-2 R ^4, with 0-2 R ^4,
0-2 propyl substituted with R ^4, ethenyl substituted with 0-2 R ^4, 0
To 2 amino been 1-propenyl substituted with R ^4, 0-2 is 2-propenyl substituted with R ^4, ethynyl substituted with 0-2 R ^4, with 0-2 R ⁴ 1-replaced
Propynyl, selected from the group of 0-2 R ⁴ in substituted 2-propynyl, and 0-1 R ^{3 d} in substituted cyclopropyl, each R ³ is appearing, C _{1 ~ 3} alkyl, OH, C _{1 ~ 3} alkoxy, F, Cl, N
R ⁵ R ^5a, NO _2, are independently selected -CN, and from the group of C (O) R ^6, or, R ³ and R ^3a form a -OCH ₂ O-together, R ^3d emergence CH ₃ , —OH, OCH ₃ , OCF ₃ , F, Cl, and −
Independently selected from the group of NR ⁵ R ^5a , each occurrence of R ^3e is CH ₃ , —OH, OCH ₃ , OCF ₃ , F, Cl, and —
NR ⁵ are independently selected from the group of R ^5a, R ⁴ _{is, Cl, F, CH 3,} CH 2 CH 3, 0~1 amino cyclopropyl substituted with R ^3e, 0 to 1 amino R ^3e in substituted 1-methyl - cyclopropyl, cyclobutyl substituted with 0-1 R ^3e, phenyl substituted with 0-2 R ^3e, and O
, N, and S containing 1 to 3 heteroatoms selected from the group selected from the group of 5 to 6 membered heterocyclic groups substituted with 0 to 1 R ^3e Is selected from the group of 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, and 2-imidazolyl. , R ⁵ and R ^5a are independently selected from the group of H, CH ₃ and C ₂ H ₅ , R ⁶ is H, OH, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ , And NR ⁵ R ^5a , R ⁷ is selected from the group of CH ₃ , C ₂ H ₅ , OCH ₃ , and OC ₂ H ₅ , and
R ⁸ is a compound selected from the group of H, cyclopropyl, and C ₂ H ₅ . 5. A compound according to claim 4, wherein the compound is of formula (Ia). [Chemical 2] 6. A compound according to claim 4, wherein the compound is of formula (Ib). [Chemical 3] 7. The compound according to claim 1, wherein the compound is 7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-5.
(Trifluoromethyl) -1,3-benzodiazepin-2-one, 6,7-difluoro-5- (2-cyclopropylethynyl) -1,5-dihydro-5- (trifluoromethyl) -1,3- Benzodiazepin-2-one, 7-chloro-5- (2-cyclopropylethenyl) -1,5-dihydro-5-
(Trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-5-
(Trifluoromethyl) -1,3-benzodiazepine-2-thione, 7-chloro-5- (2-n-butyl) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine- 2-one, 7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-3-
Methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-3-
Ethyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-3-
Cyclopropyl-5- (trifluoromethyl) -1,3-benzodiazepine-2
-One, 7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (3 -Methyl-2-butenyloxy) -1,5-dihydro-
3-Methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (3-allyloxy) -1,5-dihydro-3-methyl-5
-(Trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (3,3-dichloro-2-propenyloxy) -1,5-dihydro-3-methyl-5- (tri Fluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (2-propynyloxy) -1,5-dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepine -2-one, 7-chloro-5- (2-fluoro-6-methoxybenzyloxy) -1,5-
Dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (cyclopropylmethyloxy) -1,5-dihydro-5-
(Trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (cyclopropylmethyloxy) -1,5-dihydro-5- (trifluoromethyl) -1,3 -Benzodiazepin-2-one, 7-chloro-3-cyclopropyl-5- (cyclopropylmethoxy) -1,5
-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-3-cyclopropyl-5- (cyclopropylmethoxy)
-1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-cyclopropyl-5-propyloxy-1,5-dihydro-
5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-cyclopropyl-5-propylthio-1,5-dihydro-5
-(Trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-cyclopropyl-5-allylthio-1,5-dihydro-5-
(Trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-cyclopropyl-5-allyloxy-1,5-dihydro-5
-(Trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-cyclopropyl-5- (3-methyl-2-butenyloxy)
-1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-cyclopropyl-5-cyclobutylmethyloxy-1,5-
Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-cyclopropyl-5- (1-methylcyclopropyl) methyloxy-1,5-dihydro-5- ( Trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-cyclopropyl-5- (2-pyridyl) methyloxy-1,
5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-2-
ON, 7-chloro-3-isopropyl-5-cyclopropylmethyloxy-1,5-
Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-cyclobutyl-5-cyclopropylmethyloxy-1,5-
Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (cyclopropylmethoxy) -1,5-dihydro-3-ethyl-5- (trifluoromethyl)- 1,3-benzodiazepin-2-one, (S) -7-chloro-5- (cyclopropylmethyloxy) -1,5-dihydro-3-ethyl-5- (trifluoromethyl) -1,3-benzodiazepine -2
-One, 7-chloro-3-ethyl-5- (3-methyl-2-butenyloxy) -1,5
-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-ethyl-5-allylthio-1,5-dihydro-5- (trifluoromethyl) -1,3 -Benzodiazepin-2-one, 7-chloro-3-ethyl-5-cyclobutylmethyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro- 3-Ethyl-5-cyclopropylmethylthio-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-3-ethyl-5- (1-methylcyclopropyl ) Methyloxy-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, 7-chloro-3-propyl-5-cyclopropylmethyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-fluoro-5- ( Cyclopropylmethoxy) -1,5-dihydro-5- (
Trifluoromethyl) -1,3-benzodiazepin-2-one, 7-fluoro-3-ethyl-5-cyclopropylmethyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine- 2-one, 7-fluoro-5- (cyclobutylmethoxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-fluoro-3-ethyl-5- Cyclobutylmethyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- [2- (1-methylcyclopropyl) ethynyl] -1, 5-
Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5-cyclobutylmethyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine -2-one, 7-chloro-5- (3-methyl-2-butenyloxy) -1,5-dihydro-
5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (phenylmethyloxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine- 2-one, 7-chloro-5-[(2-pyridyl) methyloxy] -1,5-dihydro-5
-(Trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5-[(1-methylcyclopropyl) methyloxy] -1,5-
Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (3-methylphenyloxy) -1,5-dihydro-5- (
Trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (cyclopropylmethylthio) -1,5-dihydro-5- (
Trifluoromethyl) -1,3-benzodiazepin-2-one, 7-chloro-5- (propylthio) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, and From the group of 7-chloro-5- (2-propenylthio) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one or their pharmaceutically acceptable salt forms What is selected. 8. The compound according to claim 1, wherein the compound is (S) -7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-5- (trifluoromethyl). ) -1,3-Benzodiazepin-2-one, (S) -6,7-difluoro-5- (2-cyclopropylethynyl) -1,5
-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (2-cyclopropylethenyl) -1,5-dihydro-5- (tri Fluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-5- (trifluoromethyl) -1,3- Benzodiazepine-2-thione, (S) -7-chloro-5- (2-n-butyl) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S ) -7-Chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepine-2
-One, (S) -7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-3-ethyl-5- (trifluoromethyl) -1,3-benzodiazepine-2
-One, (S) -7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-3-cyclopropyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-Chloro-5-cyclopropylmethyloxy-1,5-dihydro-
3-Methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (3-methyl-2-butenyloxy) -1,5-dihydro-3- Methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (3-allyloxy) -1,5-dihydro-3-methyl-5- (tri Fluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (3,3-dichloro-2-propenyloxy) -1
, 5-Dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (2-propynyloxy) -1,5-dihydro- Three
-Methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (2-fluoro-6-methoxybenzyloxy)-
1,5-dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (cyclopropylmethyloxy) -1,5-dihydro -5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (cyclopropylmethyloxy) -1,5-dihydro-5- (trifluoromethyl)- 1,3-benzodiazepin-2-one, (S) -7-chloro-3-cyclopropyl-5- (cyclopropylmethoxy)
-1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-3-cyclopropyl-5- (cyclopropylmethoxy)
-1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-3-cyclopropyl-5-propyloxy-1,5-dihydro-5 -(Trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-3-cyclopropyl-5-propylthio-1,5-dihydro-5- (trifluoromethyl) -1, 3-benzodiazepin-2-one, (S) -7-chloro-3-cyclopropyl-5-allylthio-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, ( S) -7-chloro-3-cyclopropyl-5-allyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro 3-Cyclopropyl-5- (3-methyl-2-butenyloxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-3 -Cyclopropyl-5-cyclobutylmethyloxy-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, (S) -7-chloro-3-cyclopropyl-5- (1-methylcyclopropyl) methyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-2 -One, (S) -7-chloro-3-cyclopropyl-5- (2-pyridyl) methyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-Chloro-3-isopropyl-5-cyclopropylmethyloxy-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, (S) -7-chloro-3-cyclobutyl-5-cyclopropylmethyloxy-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, (S) -7-chloro-5- (cyclopropylmethoxy) -1,5-dihydro-
3-Ethyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (cyclopropylmethyloxy) -1,5-dihydro-3-ethyl-5 -(Trifluoromethyl) -1,3-benzodiazepine-2
-One, (S) -7-chloro-3-ethyl-5- (3-methyl-2-butenyloxy)
-1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-3-ethyl-5-allylthio-1,5-dihydro-5-
(Trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-3-ethyl-5-cyclobutylmethyloxy-1,5-
Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-3-ethyl-5-cyclopropylmethylthio-1,5-
Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-3-ethyl-5- (1-methylcyclopropyl) methyloxy-1,5-dihydro- 5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-3-propyl-5-cyclopropylmethyloxy-1,
5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-2-
On, (S) -7-fluoro-5- (cyclopropylmethoxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-fluoro- 3-ethyl-5-cyclopropylmethyloxy-1,
5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-2-
ON, (S) -7-fluoro-5- (cyclobutylmethoxy) -1,5-dihydro-
5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-fluoro-3-ethyl-5-cyclobutylmethyloxy-1,5
-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- [2- (1-methylcyclopropyl) ethynyl]-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, (S) -7-chloro-5-cyclobutylmethyloxy-1,5-dihydro-5
-(Trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (3-methyl-2-butenyloxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (phenylmethyloxy) -1,5-dihydro-5
-(Trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5-[(2-pyridyl) methyloxy] -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5-[(1-methylcyclopropyl) methyloxy]-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, (S) -7-chloro-5- (3-methylphenyloxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S)- 7-chloro-5- (cyclopropylmethylthio) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (S) -7-chloro-5- (propylthio)- 1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, and (S) -7-chloro-5- (2-propenylthio) -1,5-dihydro-5-
Selected from the group of (trifluoromethyl) -1,3-benzodiazepin-2-ones or their pharmaceutically acceptable salt forms. 9. The compound according to claim 1, wherein the compound is (R) -7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-5- (trifluoromethyl). ) -1,3-Benzodiazepin-2-one, (R) -6,7-difluoro-5- (2-cyclopropylethynyl) -1,5
-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (2-cyclopropylethenyl) -1,5-dihydro-5- (tri Fluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-5- (trifluoromethyl) -1,3- Benzodiazepine-2-thione, (R) -7-chloro-5- (2-n-butyl) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R ) -7-Chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepine-2
-One, (R) -7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-3-ethyl-5- (trifluoromethyl) -1,3-benzodiazepine-2
-One, (R) -7-chloro-5- (2-cyclopropylethynyl) -1,5-dihydro-3-cyclopropyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-
3-Methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (3-methyl-2-butenyloxy) -1,5-dihydro-3- Methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (3-allyloxy) -1,5-dihydro-3-methyl-5- (tri Fluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (3,3-dichloro-2-propenyloxy) -1
, 5-Dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (2-propynyloxy) -1,5-dihydro- Three
-Methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (2-fluoro-6-methoxybenzyloxy)-
1,5-dihydro-3-methyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (cyclopropylmethyloxy) -1,5-dihydro -5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (cyclopropylmethyloxy) -1,5-dihydro-5- (trifluoromethyl)- 1,3-benzodiazepin-2-one, (R) -7-chloro-3-cyclopropyl-5- (cyclopropylmethoxy)
-1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-3-cyclopropyl-5- (cyclopropylmethoxy)
-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-3-cyclopropyl-5-propyloxy-1,5-dihydro-5 -(Trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-3-cyclopropyl-5-propylthio-1,5-dihydro-5- (trifluoromethyl) -1, 3-benzodiazepin-2-one, (R) -7-chloro-3-cyclopropyl-5-allylthio-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, ( R) -7-Chloro-3-cyclopropyl-5-allyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro 3-Cyclopropyl-5- (3-methyl-2-butenyloxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-3 -Cyclopropyl-5-cyclobutylmethyloxy-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, (R) -7-chloro-3-cyclopropyl-5- (1-methylcyclopropyl) methyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-2 -One, (R) -7-chloro-3-cyclopropyl-5- (2-pyridyl) methyloxy-1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-3-isopropyl-5-cyclopropylmethyloxy-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, (R) -7-chloro-3-cyclobutyl-5-cyclopropylmethyloxy-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, (R) -7-chloro-5- (cyclopropylmethoxy) -1,5-dihydro-
3-Ethyl-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (cyclopropylmethyloxy) -1,5-dihydro-3-ethyl-5 -(Trifluoromethyl) -1,3-benzodiazepine-2
-One, (R) -7-chloro-3-ethyl-5- (3-methyl-2-butenyloxy)
-1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-3-ethyl-5-allylthio-1,5-dihydro-5-
(Trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-3-ethyl-5-cyclobutylmethyloxy-1,5-
Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-3-ethyl-5-cyclopropylmethylthio-1,5-
Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-3-ethyl-5- (1-methylcyclopropyl) methyloxy-1,5-dihydro- 5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-3-propyl-5-cyclopropylmethyloxy-1,
5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-2-
On, (R) -7-fluoro-5- (cyclopropylmethoxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-fluoro- 3-ethyl-5-cyclopropylmethyloxy-1,
5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-2-
ON, (R) -7-fluoro-5- (cyclobutylmethoxy) -1,5-dihydro-
5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-fluoro-3-ethyl-5-cyclobutylmethyloxy-1,5
-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- [2- (1-methylcyclopropyl) ethynyl]-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, (R) -7-chloro-5-cyclobutylmethyloxy-1,5-dihydro-5
-(Trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (3-methyl-2-butenyloxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (phenylmethyloxy) -1,5-dihydro-5
-(Trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5-[(2-pyridyl) methyloxy] -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5-[(1-methylcyclopropyl) methyloxy]-
1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepine-
2-one, (R) -7-chloro-5- (3-methylphenyloxy) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R)- 7-chloro-5- (cyclopropylmethylthio) -1,5-dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, (R) -7-chloro-5- (propylthio)- 1,5-Dihydro-5- (trifluoromethyl) -1,3-benzodiazepin-2-one, and (R) -7-chloro-5- (2-propenylthio) -1,5-dihydro-5-
Those selected from the group of (trifluoromethyl) -1,3-benzodiazepin-2-ones or their pharmaceutically acceptable salts. 10. A pharmaceutically acceptable carrier and a therapeutically effective amount of claim 1,
A pharmaceutical composition comprising the compound of 2, 3, 4, 5, 6, 7, 8 or 9 or a pharmaceutically acceptable salt form thereof. 11. A method of treating HIV infection, comprising a therapeutically effective amount of the compound of claim 1, 2, 3, 4, 5, 6, 7, 8 or 9 or a pharmaceutically acceptable salt thereof. Of a form of a. To a host in need of such treatment. 12. A method of treating HIV infection, comprising a therapeutically effective amount of (a) a compound of claim 1, 2, 3, 4, 5, 6, 7, 8 or 9, and (b). A method comprising administering at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors in combination to a host in need thereof. 13. The method according to claim 10, wherein the reverse transcriptase inhibitor is AZT, ddC, ddI, d4T, 3TC, DPC082, DPC083, D.
PC961, DPC963, AG1549, Delavirdine, Efavirenz, Nevirapine, Ro 18,893, Trovirgin, MKC-442, HBY 09
7, ACT, UC-781, UC-782, RD4-2025, and MEN
Selected from the group of 10979, wherein the protease inhibitor is saquinavir, ritonavir,
Indinavir, Amprenavir, Nelfinavir, Parinavir, BMS-23
2623, GS3333, KNI-413, KNI-272, LG-71350.
, CGP-61755, PD 173606, PD 177298, PD 17
A method selected from the group of 8390, PD 178392, U-140690 and ABT-378. 14. The method of claim 11, wherein the reverse transcriptase inhibitor is
A method selected from the group of AZT, efavirenz, and 3TC, wherein the protease inhibitor is selected from the group of saquinavir, ritonavir, nelfinavir, and indinavir. 15. The method of claim 12, wherein the reverse transcriptase inhibitor is A
A method that is ZT. 16. The method of claim 12, wherein the protease inhibitor is indinavir. 17. A pharmaceutical kit useful for the treatment of HIV infection, comprising: (a) a therapeutically effective amount in one or more containers (a). , 8 or 9 or a pharmaceutically acceptable salt form thereof, and (b) at least one compound selected from the group consisting of an HIV reverse transcriptase inhibitor and an HIV protease inhibitor. 18. Claims 1, 2, 3, 4, 5, 6, 7 for use in therapy.
, 8 or 9 or a pharmaceutically acceptable salt form thereof. 19. A method according to claim 1, 2 for producing a medicament for the treatment of HIV.
Use of the compound according to 3, 4, 5, 6, 7, 8 or 9 or a pharmaceutically acceptable salt form thereof.